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  • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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  • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
  • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • A—HUMAN NECESSITIES
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  • A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
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  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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  • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
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  • A61P13/08—Drugs for disorders of the urinary system of the prostate
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • A61P17/00—Drugs for dermatological disorders
  • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
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• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
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  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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  • A61P35/00—Antineoplastic agents
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  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system
  • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
  • A61P5/28—Antiandrogens
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  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
  • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
  • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
  • C07C235/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

• the present invention provides prodrugs of selective androgen receptor modulators (SAR s), and their use in treating or reducing the incidence of osteoporosis, a variety of ho ⁇ none-i elated conditions, conditions associated with Androgen Decline in Aging Male (ADAM); conditions associated with Androgen Decline in Female (ADIF), and musculai wasting conditions, obesity, dry eye conditions, and prostate cancer.
• SAR s selective androgen receptor modulators
• the prodrugs are also useful in oral androgen replacement therapy and male contraception.
• he androgen receptor is a ligand-activated transciiptional regulatory protein that mediates induction of male sexual development and function tlirough its activity with endogenous androgens.
• Andiogens are generally known as the male sex hormones
• the androgenic hormones are steroids that are produced in the body by the testes and the cortex of the adienal gland or can be synthesized in the laboratory. Androgenic steroids play an important iole in many physiologic processes, including the development and maintenance of male sexual characteristics such as muscle and bone mass, prostate growth, spermatogenesis, and the male hair pattern.
• the endogenous steroidal androgens include testosterone and dihydrolestosterone ("DHT").
• Testosterone is the principal steroid secreted by the testes and is the primary circulating androgen found in the plasma of males. Testosterone is converted to DHT by the enzyme 5 alpha-reductase in many peiipheral tissues DHT is thus thought lo serve as the intiacellular mediatoi for most androgen actions Because the AR is involved in male sexual development and function, the AR is a likely target for effecting male contraception or other forms of hormone replacement theiapy.
• testosterone esters have been developed which are more slowly absorbed after intramusculai injection and thus result in greater androgenic effect.
• Testosterone enanthate is the most widely used of these esters While testosterone enanthate has been valuable in terms of establishing the feasibility of hormonal agents foi male contraception, it has seveial drawbacks, including the need for weekly injections and theinstitutnce of supiaphysiologic peak levels of testosterone immediately following intramusculai injection
• Non-steroidal ligands that bind the AR and act as androgens or as antiandrogens have not been leported For this reason, lesearch on AR agonists and antagonists has focused on steroidal compounds.
• New innovative approaches are urgently needed at both the basic science and clinical levels to develop compounds which are useful for a) male contraception; b) lieatment of a variety of hormone-related conditions, for example conditions associated with ADAM, such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogo ⁇ adism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hype lasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with ADIF, such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depression, anemia
• This invention provides prodrugs of SARM compounds.
• Several of the pended SARM compounds have androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptor.
• the parent SARM compounds either alone or as a composition, aie useful foi a) male contraception; b) treatment of a variety of hoimone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogo ⁇ adism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancer; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogo ⁇ adism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood,
• G is O oi S;
• X is O;
• T is OH, OR, -NHCOCHj, or NHCOR;
• Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
• Y is CF 3 , F, I, Br, CI, CN, CR 3 or SnR 3 ;
• Q is acetamido oi trifluoroacetamido;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, CI, Br, I, alkenyl or OH;
• Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH2CH 3 , or CF 2 CF 3 .
• G in compound I is O
• T in compound I is OFI
• i in compound I is CH 3 .
• Z in compound I is NO?-
• Z in compound I is CN
• Y in compound I is CF 3 .
• Q in compound I is NHCOCHs-
• Q in compound I is in the paia position.
• Z in compound I is in the para position.
• Y in compound I is in the meta position.
• G in compound I is O, T is OH, Ri is CH 3 , Z is N0 2 , Y is CF 3 , and Q is NHCOCH 3 .
• G in compound I is O, T is OH, Z is CN, Y is CF 3 , and Q is NHCOCH3.
• the present invention provides a prodrug of a SARM compound, wherein the SARM compound is represented by a structure of foimula ll: II wheiein X is O; Z is N0 2 , CN, COOH, COR, NHCOR or CONHR; Y is CF 3 , F, I, Bi, CI, CN, CR 3 or SnR 3 ; Q is acetamido or trifluoroacetamido; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, CI, Br, I, alkenyl or OH; and Ri is CH 3 , CH 2 F,CHF 2 , CF 3 , CH 2 CH 3 , oi CF 2 CF 3
• the present invention provides a prodrug of a
• SARM compound wherein the SARM compound is represented by a spactuie of formula V:
• X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; RI is CH3, CH2F, CHF2. CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Bi, CI, alkenyl or OH; A is a ring selected from:
• B is a ring selected from:
• a and B are not simultaneously a benzene ring;
• Z is N02, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, CI, CN, CR3 or SnR3;
• QI and Q2 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NI-IS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO,
• Q3 and Q4 aie independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R oi SR, SCN, NCS, OCN, or NCO; WI is O, NH, NR, NO or S; and W2 is N or NO.
• the present invention provides a prodrug of a
• SARM compound wherein the SARM compound is represented by a stmcture of formula VI:
• X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; RI is CH3, CH2F, CHF2, CF3, CH2CH3, or CF.2CF3; R2 is F, CI, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR, SCN, NCS, OCN, or NCO; R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, CF3, Sn
• Z is N02, CN, COR, COOH, oi CONHR; Y is CF3, F, Br, CI, I, CN, or SnR3; Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
• B n is an integer of 1-4; and m is an integer of 1-3,
• the present invention provides a prodrug of a SARM compound, wherein the SARM compound is represented by a structure of formula VII:
• R2 is F, CI, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, CF3, or SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by one of the stmctures:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3 , aryl, phenyl, F, I, Br, CI, alkenyl or OH;
• Z is N02, CN, COR, COOH, or CONHR;
• Y is CF3, F, Bi, CI, I, CN, or SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or Q togethei with the benzene ring to which it is attached is a fused ring system
• a B n is an integei of 1-4; and m is an integer of 1-3.
• the present invention provides a prodrug of a
• SARM compound wheiein the SARM compound is represented by a structure of formula VIII: NHCOCH 3
• the present invention provides a prodrug of a
• SARM compound wherein the SARM compound is represented by a stmcture of formula XI:
• the present invention provides a prodiug of a
• SARM compound wherein the SARM compound is represented by a stmcture of formula XIII:
• the present invention provides a prodrug of a
• SARM compound wherein the SARM compound is represented by a structure of formula XIV:
• XIV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; RI is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is F, CI, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR, SCN, NCS, OCN, or NCO; R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, CF3,
• Z is N02, CN, COR, COOH, or CONHR;
• Y is CF3, F, Br, CI, I, CN, or SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structuie A, B or C:
• the present invention provides a prodrug of a
• SARM compound wheiein the SARM compound is represented by a stmctuie of formula XVII:
• R2 is F, Ci, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, aiyialkyl, OR, NH2, NHR, NR2, SR; R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, ' CF3, or SnR3, or R.3 together with the benzene ring to which it is attached forms a fused ring system lepiesented by one of the structures:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Bi, CI, alkenyl oi OH;
• Z is N02, CN, COR, COOH, or CONHR;
• Y is CF3, F, Bi, CI, I, CN, or SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or Q togethei with the benzene ring to which it is attached is a fused ring system
• the present invention provides a prodrug of a
• SARM compound wherein the SARM compound is represented by a structure of formula IV:
• the present invention provides a composition comprising a prodrug of a SARM of the piesent invention; and a suitable carrier or diluent
• the present invention provides a pharmaceutical composition comprising an effective amount of a prodrug of a SARM of the piesent invention; and a pharmaceutically acceptable ca ⁇ er or diluent.
• the present invention provides a method of suppiessing spermatogenesis in a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to suppress spe ⁇ production.
• the present invention provides a method of contraception of a male subject, comprising contacting the male subject with a prodiug of a SARM, in an amount effective to suppress sperm production in the male subject, thereby effecting contraception of a subject.
• the present invention provides a method of hormone therapy of a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to effect a change in an andiogen-dependent condition.
• the piesent invention provides a method of hormone replacement theiapy, comprising contacting the subject with a prodiug of a SARM, in an amount effective to effect a change in an androgen-dependenl condition
• the present invention provides a method of treating a subject having a hormone-related condition, comprising contacting the subject with a prodrug of a SARM, in an amount effective to effect a change in a hoimone-related condition,
• the present invention provides a method of treating a subject suffering from a prostate cancel in a subject, comprising contacting the subject with a prodiug of a SARM, in an amount effective to treat a prostate cancel in the subject.
• the piesent invention provides a method of i educing an incidence of a prostate cancer in a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to reduce an incidence of a prostate cancer in the subject.
• the piesent invention piovides a method of delaying a progression of a prostate cancer in a subject having prostate cancel, comprising contacting the subject with a prodrug of a SARM, in an amount effective to delay the progression of a prostate cancer in the subject
• the present invention provides a method of reducing an incidence of a recurrence of a prostate cancer in a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to reduce the incidence of a recuixence of a prostate cancer in the subject.
• the present invention provides a method of heating a dry eye condition in a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to treat the dry eye condition in the subject
• the present invention provides a method of reducing an incidence of a dry eye condition in a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to reducing an incidence of the diy eye condition in the subject
• the piesent invention provides a method of binding an androgen receptor (AR), comprising contacting the AR with a prodrug of a SARM
• the piesent invention provides a prodrug of a selective androgen receptor modulatoi (SARM) compound, wheiein the piodiug is represented by a structure of formula II-B:
• X is a bond, O, CH2, NH, Se, PR, NO or NR
• Z is N02, CN, COOH, COR, NHCOR oi CONHR
• Y is CF3, F, I, Bi, CI, CN, CR3 or SnR3
• Q is alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONFIR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, or NCO; or Q togethei with the benzene ring to which it is attached is a fused ring system tepresented by structure A, B or C:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; wherein RI is as defined below, and wheiein the SARM compound is bound to any suitable atom of RI .
• the present invention provides a piodmg of a selective androgen leceptor modulator (SARM) compound, wherein the prodrug is represented by a stmcture of formula V-B:
• SARM selective androgen leceptor modulator
• V-B whei ein X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; T is CH3, CH2F, CHF2, CF3, CH2CH3, or CF.2CF3; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; A is a ring selected from:
• B is a ring selected from: wherein A and B aie not simultaneously a benzene ring; Z is N02, CN, COOH, COR, NHCOR or CONHR; Y is CF3, F, I, Br, CI, CN, CR3 or SnR3; QI and Q2 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO,
• Q3 and Q4 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, OCN, oi NCO; Wl is O, NH, NR, NO o S; W2 is N or NO, wherein RI is as defined below, and wherein the SARM compound is bound to any suitable atom of RI .
• the present invention provides a prodiug of a
• R2 is F, CI, Bi, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, al yl, aiylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, CI, Bi, I, CN, N02, COR, COOH, CONHR, CF3, or S ⁇ R3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by one of the structures:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aiyl, phenyl, F, I, Bi, CI, alkenyl or OH;
• Z is N02, CN, COR, COOH, or CONHR;
• Y is CF3, F, Br, CI, I, CN, or SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, oi SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by stracture A B
• the present invention provides a prodrug of a
• the present invention provides a prodrug of a
• SARM compound wheiein the prodrug is represented by a structure of foimula XI-B:
• RI is as defined below, and wherein the SARM compound is bound to any suitable atom of RI .
• the present invention provides a prodrug of a selective androgen receptor modulator (SARM) compound, wherein the prodrug is represented by a stmcture of fo ⁇ mila XIII-B:
• RI is as defined below; and wherein the SARM compound is bound to any suitable atom of RI.
• the present invention provides a prodiug of a selective androgen receptor modulator (SARM) compound, wherein the prodmg is represented by a structure of formula IV-B:
• RI is one of the structures depicted below, and wherein the SARM compound is bound to any suitable atom of RI .
• the SARM modification in the above structures designated by a number-"B" is one of the structures: and wheiein R7 is O or CH2; R ⁇ is N or CH; R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO, a bond to the SARM compound at the indicated location, wherein Q3 and Q4 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, S ⁇ R3, NR2, NHCOCH3, NHCOCF3,
• the present invention provides a prodmg of a
• X is a bond, O, CH2, NH, Se, PR, NO or NR;
• Z is N02, CN, COOH, COR, NHCOR, or CONHR;
• Y is CF3, F, I, Br, CI, CN, CR3 or SnR3;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; and either: (a) Q is one of the structures: wherein R7 is O or CH2; R8 is N or CH; R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR., CONHR, N
• Q3 and Q4 aie independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHC0CH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, OCN, or NCO; wherein the SARM compound is bound to any suitable atom of Q; or
• the present invention provides a prodrug of a
• X is a bond, O, CH2, NH, Se, PR, NO or NR;
• Q is alkyl, F, I, Bi, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, or NCO; or Q together with the benzene ring to which it is attached is a fused ring system lepresented by stmcture A, B or C:
• a B R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aiyl, phenyl, F, I, Bi, CI, alkenyl or OH; and either: (a) Z is one of the stmctures:
• R7 is O oi CH2;
• R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO, a bond to the SARM compound at the indicated location,
• Q3 and Q4 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, OCN, or NCO; wheiein the SARM compound is bound to any suitable atom of Z; or
• the present invention provides a piodmg of a
• X is a bond, O, CH2, NH, Se, PR, NO or NR; Z is N02, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, CI, CN, CR3 or SnR3; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; and either: (a) Q is one of the structures:
• R7 is 0 or CH2; RS is o CH; R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Bi, CI, CF3, CN, CR3, SnR3, NR2, NHC0CH3, NHC0CF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, 0S02R, S02R, SR, SCN, NCS, OCN, NCO, a bond to the SARM compound at the indicated location,
• Q3 and Q4 are independently of each oilier a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R oi SR, SCN, NCS, OCN, oi NCO; wheiein the SARM compound is bound to any suitable atom of Q; or (b) Q, togethei with a B ring lo which it is attached, is a fused ring system represented by one of the structures:
• the present invention provides a prodmg of a
• LII wheiein X is a bond, O, CH2, NFI, Se, PR, NO or NR;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; and either: (a) Z is one of the stmctures:
• R7isOorCH2; RSisNorCH; R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3,NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO, a bond to the SARM compound at the indicated location,
• Q3 and Q4 aie independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R oi SR, SCN, NCS, OCN, oi NCO; wherein the SARM compound is bound to any suitable atom of Z; or (b) Z, togethei with a B ring to which it is attached, is a fused ring system lepiesented by one of the structures:
• Figuie 1 Synthesis scheme of Compound VIII.
• Figure 2 Synthesis scheme of a Compound XI and its prodrug.
• Figure 3 Androgenic and Anabolic activity of Compound VIII. Rats were left untreated (intact contiol), castrated (castrated control), heated with testosterone piopionate (TP), or tieated with Compound VIII, and the body weight gain as well as the weight of androgen-responsive tissues (prostate, semimal vesicles and levator ani muscle) was determined
• Figure 4 Androgenic and Anabolic activity of Compound VIII, Rats were left untreated (intact control), castrated (castrated control), treated with 0.1, 0.3, 0.5, 0.75 and 1 0 mg/day TP, oi treated with 0,1, 0.3, 0.5, 0,75 and 1.0 mg/day Compound VIII, and the weight of androgen-responsive tissues (prostate, semimal vesicles and levator ani muscle) was dete ⁇ nined.
• Figure 5 Androgenic and Anabolic activity of Compound IX. Rats were left untreated (intact control), cas ated (castrated control), treated with 0.1, 0.3, 0.5, 0,75 and 1 0 mg/day TP, or treated with 0.1, 0.3, 0.5, 0,75 and 1,0 mg/day Compound III, and the weight of androgen-responsive tissues (prostate, semimal vesicles and levator ani muscle) was determined.
• Figure 6 Aveiage plasma concentration-time profiles of Compound VIII in beagle dogs aftei IV administiation at 3 and 10 mg/kg.
• Figure 7 Average plasma concentration-time profiles of Compound VIII in beagle dogs after PO administration as solution at 10 mg kg.
• Figure 8 Average plasma concentration-time profiles of Compound VIII in beagle dogs after IV administration as capsules at mg/ g.
• this invention provides prodrugs of selective androgen receptor modulators (SARM) compounds.
• SARM selective androgen receptor modulators
• the parent SARM compounds are useful for a) male contraception; b) treatment of a variety of hormone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, eiectile dysfunction, hypogonadism, osteoporosis, hah loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancel ; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction, decreased sexual libido, hypogonadism, sarcopenia, osteopenia, osteoporosis, alterations in cognition and mood, depiession, anemia, hair loss, obesity, endometriosis, breast cancer, uterine cancer and ovarian cancer; d) treatment and/or prevention of acute and/or chronic muscular wasting
• the present invention provides a prodrug of a
• G is O oi S; is O; T is OH, OR, -NHCOCH3, or NHCOR; Z is N0 2 , CN, COOH, COR, NHCOR or CONHR; Y is CF 3 , F, I, Br, CI, CN, CR 3 or SnR 3 ; Q is acetamido or tiifluoroacetamido; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, CI, Br, I, alkenyl or OH; and R, is CH 3 , CH 2 F, CHF 2 ,CF 3l CH 2 CH 3 , or CF 2 CF 3 .
• G in compound I is O
• T in compound I is OH.
• Rj in compound I is CH 3 .
• Z in compound I is N0 2 ,
• Z in compound I is CN.
• Y in compound I is CF 3 .
• Q in compound I is NHCOCH 3 .
• Q in compound I is in the para position.
• Z in compound I is in the paia position.
• Y in compound I is in the meta position.
• G in compound I is O, T is OH, Ri is CH 3 , Z is N0 2 , Y is CF 3 , and Q is NHCOCH 3 .
• G in compound I is O, T is OH, Z is CN, Y is CF 3 , and Q is NHCOCH3.
• the present invention provides a prodiug of a SARM compound, wheiein the SARM compound is repiesented by a facilitatorctuie of formula II:
• X is O
• Z is N0 2 , CN, COOH, COR, NHCOR or CONHR
• Y is CF 3 , F, I, Bi, CI, CN, CR 3 or SnR 3
• Q is acetamido or trifluoroacetamido
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aiyl, phenyl, F, CI, Br, I, alkenyl or OH
• Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH2CH3, or CF,CF 3 .
• Z in compound II is N0 2 . In another embodiment, Z in compound II is CN. In another embodiment, Y in compound II is CF 3 . In another embodiment, Q in compound II is NHCOCH 3 In another embodiment, Z in compound II is N0 2 , Y is CF3, and Q is NHCOCH 3 , In another embodiment, Z in compound II is CN, Y is CF 3> and Q is NHCOCH3.
• the SARM piodmg of the present invention has in-vivo androgenic and anabolic activity of a nonsteroidal ligand for the androgen receptoi
• the SARM prodrug of the present invention is an androgen 1 eceptor agonist
• a prodrug of the piesent invention has a modification that increases an aqueous solubility of the prod g relative to the parent SARM compound.
• a prodrug of the present invention has a modification that decieases an aqueous solubility of the prodrug relative to the patent SARM compound.
• a prodmg of the present invention has a modification that increases a bioavailability of the prodmg relative to the SARM
• the bioavailability is an oral bioavailability
• a prodiug of the piesent invention has a modification that decreases a toxicity of the prodrug relative to the SARM
• the present invention provides a prodiug of a SARM compound, wherein the SARM compound is represented by a structure of foimula V:
• X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; Rl is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aiyl, phenyl, F, I, Br, CI, alkenyl or OH; A is a ring selected from:
• B is a ring selected from:
• a and B are not simultaneously a benzene ring;
• Z is N02, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, CI, CN, CR3 or SnR3;
• QI and Q.2 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHSO2CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO,
• Q3 and Q4 are independently of each other a hydrogen, alkyl, F, I, Bi, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, OCN, or NCO; WI is O, NH, NR, NO or S; and W2 is N or NO,
• the piesent invention provides a prodrug of a
• X is a bond, O, CH2, NH, Se, PR, NO oi NR; G is O or S; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Bi, CI, alkenyl or OH; Rl is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R2 is F, CI, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR, SCN, R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, oi R3
• Z is N02, CN, COR, COOH, oi CONHR;
• Y is CF3, F, Bi, CI, I, CN, or SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or
• Q togethei with the benzene ring to which it is attached is a fused ring system represented by stmctuie A, B or C:
• the present invention provides a prodiug of a
• R2 is F, CI, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, CF3, or SnR3, or R3 together with the benzene ring to which it is attached fonns a fused ling system represented by one of the stmctures:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH;
• Z is N02, CN, COR, COOH, oi CONHR;
• Y is CF3, F, Bi, CI, I, CN, oi SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or Q together with the benzene ring to which it is attached is a fused ring system represented
• the present invention provides a piodmg of a SARM compound, wherein the SARM compound is represented by a stmctuie of foimula VIII: NHCOCH 3
• the present invention provides a prodmg of a
• SARM compound wherein the SARM compound is represented by a stracture of formula XI:
• the present invention provides a prodrug of a
• the present invention provides a prodrug of a
• SARM compound wherein the SARM compound is represented by a stmctuie of foimula XIV:
• XIV wherein X is a bond, O, CH2, NH, Se, PR, NO or NR; T is OH, OR, -NHCOCH3, or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; Rl is CH3, CH.2F, CHF2, CF3, CH2CH3, or CF2CF3; is F, CI, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR, SCN, NCS, OCN, or NCO; R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, CF3, SnR3, or R3
• Z is N02, CN, COR, COOH, or CONHR;
• the present invention provides a prodmg of a
• SARM compound wherein the SARM compound is represented by a spactuie of formula XVII:
• W is F, Ci, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR; R3 is F, CI, Br, I, CN, N02, COR, COOH, CONHR, CF3, or SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by one of the structures:
• Benzene ring is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH;
• Z is N02, CN, COR, COOH, or CONHR;
• Y is CF3, F, Br, CI, I, CN, or SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or Q together with the benzene ring to which it is attached is a fused ring
• the present invention provides a prodiug of a
• SARM compound wheiein the SARM compound is represented by a stmcture of foimula IV:
• the pended SARM compound is a compound of one of the above foimulas wherein Z is N0 2
• the parent SARM compound is a compound of one of the above fo ⁇ nulas wherein Z is CN
• the pending SARM compound is a compound of one of the above foimulas wherein Z is COOH.
• the parent SARM compound is a compound of one of the above formulas wherein Z is COR
• the parent SARM compound is a compound of one of the above foimulas wheiein Z is NHCOR
• the parent SARM compound is a compound of one of the above formulas wherein Z is CONHR.
• the pended SARM compound is a compound of one of the above foimulas wherein Y is CF 3 -
• the parent SARM compound is a compound of one of the above formulas wherein Y is F
• the parent SARM compound is a compound of one of the above formulas wherein Y is I.
• the pended SARM compound is a compound of one of the above foimulas wheiein Y is Br
• the parent SARM compound is a compound of one of the above formulas wheiein Y is CI
• the parent SARM compound is a compound of one of the above foimulas wheiein Y is CN.
• the pended SARM compound is a compound of one of the above formulas wheiein Y is CR 3 .
• the pended SARM compound is a compound of one of the above foimulas wherein Y is S11R 3 ,
• the parent SARM compound is a compound of one of the above formulas wheiein Q is NHCOCH 3 .
• the parent SARM compound is a compound of one of the above foimulas wherein Q is F.
• the pending SARM compound is a compound of one of the above formulas wherein Q is alkyl.
• the parent SARM compound is a compound of one of the above formulas wheiein Q is I.
• the parent SARM compound is a compound of one of the above formulas wherein Q is Br
• the pended SARM compound is a compound of one of the above formulas wherein Q is CI
• the parent SARM compound is a compound of one of the above formulas wheiein Q is CF 3
• the pending SARM compound is a compound of one of the above formulas wherein Q is CN
• the parent SARM compound is a compound of one of the above foimulas wherein Q is CR 3
• the parent SARM compound is a compound of one of the above foimulas wherein Q is S11R 3
• the pended SARM compound is a compound of one of the above formulas wherein Q is NR 2
• the pended SARM compound is a compound of one of the above formulas wherein Q is NFICOCF 3
• the parent SARM compound is a compound of one of the above formulas wherein Q is NHCOOR
• the pending SARM compound is a compound of one of the above formulas wherein Q is OCONHR
• the parent SARM compound is a compound ol one of the above foimulas wheiein Q is CONHR
• the parent SARM compound is a compound of one of the above formulas wheiein Q is NHCSCH 3
• the parent SARM compound is a compound of one of the above formulas wherein Q is NHCSCF 3 .
• the pended SARM compound is a compound of one of the above formulas wheiein Q is NHCSR In anothei embodiment, the pended SARM compound is a compound of one of the above fo ⁇ nulas wherein Q is NHSO 2 CH 3 In another embodiment, the pending SARM compound is a compound of one of the above formulas wherein Q is NHS0 2 R. In another embodiment, the parent SARM compound is a compound of one of the above foimulas wherein Q is OR.
• the parent SARM compound is a compound of one of the above formulas wherein Q is COR
• the pended SARM compound is a compound of one of the above foimulas wherein Q is OCOR
• the parent SARM compound is a compound of one of the above fo ⁇ nulas wheiein Q is OS0 2 R
• the parent SARM compound is a compound of one of the above fo ⁇ nulas wherein Q is S0 2 R.
• the pended SARM compound is a compound of one of the above formulas wheiein Q is SR
• the parent SARM compound is a compound of one of the above foimulas wherein Q is SCN.
• the parent SARM compound is a compound of one of the above fo ⁇ nulas wherein Q is NCS.
• the parent SARM compound is a compound of one of the above formulas wheiein Q is OCN.
• the pending SARM compound is a compound of one of the above formulas wherein Q is NCO
• the parent SARM compound is a compound of one of the above formulas wherein R is alkyl
• the pended SARM compound is a compound of one of the above formulas wheiein R is haloalkyl
• the pending SARM compound is a compound of one of the above foimulas wheiein R is dihaloalkyl
• the pending SARM compound is a compound of one of the above foimulas wherein R is trihaloalkyl.
• the parent SARM compound is a compound of one of the above foimulas wherein R is CH 2 F.
• the parent SARM compound is a compound of one of the above formulas wherein R is CHF 2 .
• the pending SARM compound is a compound of one of the above formulas wherein R is CF 3
• the parent SARM compound is a compound of one of the above formulas wherein R is CF 2 CF 3 .
• the parent SARM compound is a compound of one of the above foimulas wheiein R is aryl.
• the parent SARM compound is a compound of one of the above foimulas wherein R is phenyl
• the parent SARM compound is a compound of one of the above formulas wheiein R is F
• the parent SARM compound is a compound of one of the above foimulas wherein R is I
• the pended SARM compound is a compound of one of the above formulas wheiein R is Bi
• the pended SARM compound is a compound of one of the above foimulas wheiein R is CI
• the pended SARM compound is a compound of one of the above formulas wherein R is alkenyl
• the pended SARM compound is a compound of one of the above foimulas wheiein R is OH
• the pended SARM compound is a compound of one of the above formulas wherein R 1 is CH 3 .
• the parent SARM compound is a compound of one of the above formulas wherein R 1 is CH 2 F
• the pended SARM compound is a compound of one of the above fo ⁇ nulas wherein R 1 is CHF 2 .
• the parent SARM compound is a compound of one of tire above formulas wherein R ! is CF 3 .
• the pending SARM compound is a compound of one of the above formulas wherein R 1 is CH 2 CH 3 .
• the parent SARM compound is a compound of one of the above fo ⁇ nulas wherein R 1 is CF 3 CF 3 .
• a prodiug of the piesent invention has a modification that alters an aqueous solubility of the prodrug relative to the parent SARM compound.
• a prodrug of the present invention has a modification that increases a bioavailability of the piodiug relative to the SARM.
• the bioavailability is an oial bioavailability
• the piesent invention provides a composition comprising a prodrug of a SARM of the present invention; and a suitable carrier 01 diluent.
• the present invention provides a pharmaceutical composition comprising an effective amount of a prodmg of a SARM of the present invention; and a phaimaceutically acceptable carrier or diluent
• the present invention provides a method of suppressing spermatogenesis in a subject, comprising contacting the subject with a piodiug of a SARM, in an amount effective to suppress speim production.
• the present invention provides a method of conhaception of a male subject, comprising contacting the male subject with a prodmg of a SARM, in an amount effective to suppress sperm production in the male subject, theieby effecting contraception of a subject
• the piesent invention provides a method of hormone therapy of a subject, comprising contacting the subject with a prodmg of a SARM, in an amount effective to effect a change in an androgen-dependent condition
• the piesent invention provides a method of hormone replacement therapy, comprising contacting the subject with a prodrug of a SARM, in an amount effective to effect a change in an andiogen-dependent condition
• the present invention provides a method of treating a subject having a ho ⁇ none-related condition, comprising contacting the subject with a prodrug of a SARM, in an amount effective to effect a change in a hoimone-related condition.
• the present invention provides a method of treating a subject having a prostate cancer, comprising contacting the subject with a piodiug of a SARM, in an amount effective to treat a prostate cancel in the subject
• the present invention provides a method of reducing an incidence of a prostate cancer in a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to leduce an incidence of a prostate cancer in the subject
• the present invention provides a method of delaying a progression of a prostate cancer in a subject having prostate cancel, comprising contacting the subject with a prodrug of a SARM, in an amount effective to delay the progiession of a prostate cancer in the subject
• the present invention provides a method of i educing an incidence of a recurrence of a prostate cancer in a subject, comprising contacting the subject with a prodiug of a SARM, in an amount effective to reduce the incidence of a lecu ⁇ ence of a prostate cancer in the subject.
• the present invention provides a method of treating a dry eye condition in a subject, comprising contacting the subject with a prodmg of a SARM, in an amount effective to treat the dry eye condition in the subject.
• the present invention provides a method of reducing an incidence of a dry eye condition in a subject, comprising contacting the subject with a prodrug of a SARM, in an amount effective to reducing an incidence of the dry eye condition in the subject.
• the present invention provides a method of binding an androgen receptor (AR), comprising contacting the AR with a prodiug of a SARM.
• AR androgen receptor
• the present invention provides a prodrug of a selective androgen receptor modulator (SARM) compound, wherein the prodiug is represented by a structure of foimula II-B:
• X is a bond, O, CH2, NH, Se, PR, NO or NR
• Z is N02, CN, COOH, COR, NHCOR or CONHR
• Y is CF3, F, I, Br, CI, CN, CR3 or SnR3
• Q is alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, or NCO; or Q together with the benzene ring to which it is attached is a fused ring system represented by stmcture A, B or C:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CI-IF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; wherein Rl is as defined below, and wherein the SARM compound is bound to any suitable atom of Rl.
• the piesent invention provides a prodmg of a selective androgen receptoi modulatoi (SARM) compound, wherein the prodrug is represented by a structuie of formula V-B:
• V-B wherein X is a bond, O, CH2, NH, Se, PR, NO or NR; G is O or S; T is CH3, CH2F, CHF2, CF3, CH2CH3, or CF2CF3; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF.3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; A is a ring selected from:
• B is a ring selected from:
• Z is N02, CN, COOH, COR, NHCOR or CONHR;
• Y is CF3, F, I, Br, CI, CN, CR3 or SnR3;
• QI and Q2 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3.
• Q3 and Q4 are independently of each other a hydrogen, alkyl, F, I, Bi, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH.3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, OCN, or NCO; Wl is O, NH, NR, NO or S; W2 is N or NO, wherein Rl is as defined below, and wherein the SARM compound is bound to any suitable atom of Rl .
• the present invention provides a prodmg of a
• R2 is F, CI, Br, I, CH3, CF3, OH, CN, N02, NHCOCH3, NHCOCF3, NHCOR, alkyl, arylalkyl, OR, NH2, NHR, NR2, SR;
• R3 is F, Ci, Br, I, CN, NO2, COR, COOH, CONHR, CF3, or SnR3, or R3 together with the benzene ring to which it is attached forms a fused ring system represented by one of the structures:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH;
• Z is N02, CN, COR, COOH, or CONHR;
• Y is CF3, F, Br, CI, I, CN, or SnR3;
• Q is H, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OH, OR, COR, OCOR, OS02R, S02R, or SR; or Q together with the benzene ring to which it is attached is a fused ring system lepresented by structure A, B or C:
• the present invention provides a prodrug of a
• V ⁇ I-B wherein Rl is as defined below, and wherein the SARM compound is bound to any suitable atom of RL
• the present invention provides a prodmg of a
• the present invention provides a prodmg of a selective androgen receptor modulator (SARM) compound, wherein the prodrug is repiesented by a stracture of formula XIII-B:
• SARM selective androgen receptor modulator
• the present invention provides a prodmg of a selective androgen receptor modulatoi (SARM) compound, wheiein the prodmg is represented by a structuie of foimula IV-B:
• SARM selective androgen receptor modulatoi
• Rl is one of the structures depicted below, and wheiein the SARM compound is bound to any suitable atom of Rl.
• R7 is 0 or CH2;
• R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, S ⁇ R3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO, a bond, O-linkage, orN-linkage to the SARM compound al the indicated location, wherein Q3 and Q4 are independently of each othei a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR
• the present invention provides a prodrug of a SARM compound, wherein the prodmg is represented by a stmcture of formula II:
• X is a bond, O, CH2, NH, Se, PR, NO or NR; Z is N02, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, CI, CN, CR3 or SnR3; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or OH; and eithei : (a) Q is one of the structures: wherein R7 is O or CH2; R8 is N or CH; R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHC0CH3, NHC0CF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, N
• Q3 and Q4 are independently of each othei a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R oi SR, SCN, NCS, OCN, oi NCO; wherein the SARM compound is bound to any suitable atom of Q;
• the present invention provides a prodrug of a
• X is a bond, O, CH2, NH, Se, PR, NO or NR
• Q is alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHC0CH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NFICSCH3, NHCSCF3, NHCSR, NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, or NCO; or Q togethei with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl oi OH; and either: (a) Z is one of the s uctures:
• R7 is O or CH2;
• RS is N o CH;
• R5, R6, and R9 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R, SR, SCN, NCS, OCN, NCO, a bond, 0-linkage, or N-linkage to the SARM compound at the indicated location,
• Q3 and Q4 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, wherein the SARM compound is bound to any suitable atom of Z;
• the present invention provides a prodrug of a
• X is a bond, O, CH2, NH, Se, PR, NO or NR; Z is N02, CN, COOH, COR, NHCOR, or CONHR; Y is CF3, F, I, Br, CI, CN, CR3 or SnR3; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CFI2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Br, CI, alkenyl or' OH; and either: (a) Q is one of the structures:
• Q3 and Q4 are independently of each othei a hydrogen, alkyl, F, I, Bi, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, OCN, oi NCO; wherein the SARM compound is bound to any suitable atom of Q;
• the present invention provides a prodmg of a
• LII wherein X is a bond, O, CH2, NH, Se, PR, NO oi NR;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, F, I, Bi, CI, alkenyl or OH; and either: (a) Z is one of the stmctures:
• Q3 and Q4 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF3, CN, CR3, SnR3, NR2, NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR NHS02CH3, NHS02R, OR, COR, OCOR, OS02R, S02R or SR, SCN, NCS, OCN, oi NCO; wherein the SARM compound is bound to any suitable atom of Z; or (b) Z, together with a B ring to which it is attached, is a fused ring system represented by one of the stmctures:
• the present invention provides a synthetic intermediate represented by a structure of formula LIII:
• Z is N0 2 , CN, COR, COOH, or CONHR; Y is CF 3 , F, Br, CI, I, CN, or SnR 3 ; and Q is H, alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHS0 2 CFI 3 , NHS0 2 R, OH, OR, COR, OCOR, OS0 2 R, S0 2 R, 01 SR; 01 Q together with the benzene ring to which it is attached is a fused ting system repiesented by stmctuie A, B or C:
• the piesent invention provides a prodmg derived from the above synthetic inteimediate, wherein a methyl group is replaced by one of the structures:
• the present invention provides a synthetic inteimediate represented by a stmcture of foimula LIV: LIV wherein: Z is N0 2 , CN, COR, COOH, or CONHR; Y is CF 3 .
• Q is H, alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO2R, OH, OR, COR, OCOR, OS0 2 R, S0 2 R, 01 SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by stmcture A, B or C:
• a B W is N0 2 01 OH
• N is 1, 2, 3, or 4
• the piesent invention provides a prodmg derived from the above synthetic intermediate, wherein W is replaced by one of the stmctures:
• the piesent invention provides a synthetic intermediate lepresented by a structure of formula LV:
• Z is N0 2 , CN, COR, COOH, or CONHR;
• Y is CF 3.
• Q is H, alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3 , NR 2l NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCFs, NFICSR, NHS0 2 CH 3 , NHS0 2 R, OH, OR, COR, OCOR, OS0 2 R, S0 2 R, or SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by structure A, B or C: and N is 1, 2, 3, or 4.
• the present invention provides a piodmg derived from the above synthetic inteimediate, wherein an OH group is leplaced by one of the structures:
• the SARM prodrug is a compound of one of the above foimulas wherein Z is N0 2 .
• the SARM piodmg is a compound of one of the above formulas wherein Z is CN.
• the SARM prodiug is a compound of one of the above formulas wherein Z is COOH
• the SARM prodmg is a compound of one of the above foimulas wherein Z is COR.
• the SARM prodmg is a compound of one of the above formulas wheiein Z is NHCOR.
• the SARM prodmg is a compound of one of the above formulas wherein Z is CONHR.
• the SARM prodrug is a compound of one of the above formulas wheiein Y is CF 3
• the SARM prodrug is a compound of one of the above foimulas wherein Y is F
• the SARM piodiug is a compound of one of the above formulas wherein Y is I
• the SARM prodmg is a compound of one of the above formulas wherein Y is Bi.
• the SARM prodrug is a compound of one of the above formulas wherein Y is CI
• the SARM prodmg is a compound of one of the above formulas wherein Y is CN.
• the SARM prodmg is a compound of one of the above formulas wheiein Y is CR 3 - hi anothei embodiment, the SARM prodmg is a compound of one of the above formulas wheiein Y is SnR 3 .
• the SARM prodrug is a compound of one of the above foimulas wherein Q is NHCOCH 3
• the SARM piodmg is a compound of one of the above foimulas wherein Q is F.
• the SARM piodiug is a compound of one of the above formulas wherein Q is alkyl.
• the SARM prodrug is a compound of one of the above foimulas wherein Q is I.
• the SARM prodiug is a compound of one of the above formulas wherein Q is Br In anothei embodiment, the SARM prodiug is a compound of one of the above foimulas wherein Q is CI In another embodiment, the SARM prodrug is a compound of one of the above formulas wherein Q is CF 3 .
• the SARM prodrug is a compound of one of the above formulas wherein Q is CN In another embodiment, the SARM prodrug is a compound of one of the above foimulas wheiein Q is CR 3 In another embodiment, the SARM prodmg is a compound of one of the above foimulas wherein Q is SriRj, In another embodiment, the SARM prodiug is a compound of one of the above formulas wherein Q is NR 2 .
• the SARM prodmg is a compound of one of the above formulas wherein Q is NHCOCF 3
• the SARM prodrug is a compound of one of the above formulas wherein Q is NHCOR
• the SARM prodrug is a compound of one of the above formulas wheiein Q is NFICONHR
• the SARM prodmg is a compound of one of the above formulas wherein Q is NHCOOR.
• the SARM prodmg is a compound of one of the above formulas wheiein Q is OCONHR In anothei embodiment, the SARM prodmg is a compound of one of the above formulas wheiein Q is CONHR In another embodiment, the SARM prodrug is a compound of one of the above formulas wherein Q is NHCSCH 3 .
• the SARM prodrug is a compound of one of the above foimulas wherein Q is NHCSCF 3
• the SARM prodiug is a compound of one of the above foimulas wherein Q is NHCSR
• the SARM prodmg is a compound of one of the above formulas wherein Q is NFISO 2 CH 3
• the SARM prodrug is a compound of one of the above foimulas wheiein Q is NHS0 2 R.
• the SARM prodrug is a compound of one of the above formulas wherein Q is OR, In anothei embodiment, the SARM piodiug is a compound of one of the above formulas wheiein Q is COR In anothei embodiment, the SARM prodrug is a compound of one of the above formulas wherein Q is OCOR In anothei embodiment, the SARM piodiug is a compound of one of the above fo ⁇ nulas wherein Q is OS0 R In another embodiment, the SARM prodrug is a compound of one of the above foimulas wheiein Q is S0 2 R.
• the SARM prodiug is a compound of one of the above formulas wheiein Q is SR. In another embodiment, the SARM prodiug is a compound of one of the above foimulas wheiein Q is SCN In anotliei embodiment, the SARM prodmg is a compound of one of the above foimulas wherein Q is NCS. In another embodiment, the SARM prodrug is a compound of one of the above foimulas wherein Q is OCN.
• the SARM prodrug is a compound of one of the above formulas wherein Q is NCO 00113]In anothei embodiment, the SARM prodrug is a compound of one of the above formulas wheiein R is alkyl. In another embodiment, the SARM prodiug is a compound of one of the above formulas "'herein R is haloalkyl. In anothei embodiment, the SARM prodrug is a compound of one of the above formulas wherein R is dihaloalkyl. In another embodiment, the SARM prodiug is a compound of one of the above foimulas wherein R is trihaloalkyl.
• the SARM prodiug is a compound of one of the above formulas wheiein R is CH 2 F i anothei embodiment, the SARM prodrug is a compound of one of the above foimulas wheiein R is CHF 2 .
• the SARM prodrug is a compound of one of the above formulas wherein R is CF 3
• the SARM prodiug is a compound of one of the above formulas wherein R is CF 2 CF 3
• the SARM prodmg is a compound of one of the above formulas wherein R is aiyl
• the SARM prodiug is a compound of one of the above foimulas wheiein R is phenyl.
• the SARM prodrug is a compound of one of the above formulas wherein R is F
• the SARM prodrug is a compound of one of the above foimulas wheiein R is I.
• the SARM prodmg is a compound of one of the above foimulas wherein R is Br.
• the SARM prodrug is a compound of one of the above formulas wherein R is CI
• the SARM prodrug is a compound of one of the above formulas wherein R is alkenyl
• the SARM prodiug is a compound of one of the above formulas wherein R is OH,
• the SARM prodmg is a compound of one of the above formulas wherein R 1 is CH 3 .
• the SARM prodiug is a compound of one of the above formulas wherein R 1 is CH 2 F.
• the SARM piodiug is a compound of one of the above formulas wherein R 1 is CHF 2 .
• the SARM piodmg is a compound of one of the above formulas wherein R 1 is CF 3 .
• the SARM prodmg is a compound of one of the above formulas wherein R 1 is CH 2 CH 3 .
• the SARM piodmg is a compound of one of the above foimulas wheiein R 1 is CF 2 CF 3
• each substituent of each of X, Y, Z, G, T, Q, R and R 1 , for each of the above formulas, represents a separate embodiment of the present invention. Fuitlier, each position enumerated above of each of the above substituents represents a separate embodiment of the piesent invention. Further, each number enumerated above of each of the above integeis represents a separate embodiment of the present invention.
• the symbol "O" in stractures of the present invention when depicted with one single bond, refeis, in one embodiment, to an -OH. In anotlier embodiment, it refers to an O-. Each possibility represents a separate embodiment of the piesent invention.
• the present invention provides a prodiug of one of the pended SARM compounds depicted below (in the section "Selective Androgen Receptoi Modulators"), wherein the prodmg modification is attached as depicted for the above prodmgs.
• the present invention provides a method of increasing a bioavailability of a SARM compound, comprising attaching to a chiral carbon of the SARM one of the structures:
• bioavailability refers to a tissue-specific bioavailability
• bioavailability refers to any othei type of bioavailability known in die art.
• the present invention provides a method of increasing a bioavailability of a SARM compound, comprising attaching to an A ring or a B ring of said SARM one of the structures described above as attached to the chiial carbon.
• the present invention provides a method of altering a solubility of a SARM compound, comprising attaching to a chiral carbon of said SARM one of the structures one of the stmctures described above in the method of increasing bioavailability.
• the present invention provides a method of altering a solubility of a SARM compound, comprising attaching to a chiral carbon of said SARM one of the stmctures one of the structures described above in the method of increasing bioavailability
• the present invention provides a method of deci easing a toxicity of a SARM compound, comprising attaching to a chiral carbon of said SARM one of the stmctures described above in the method of increasing bioavailability
• the piesent invention provides a method of decreasing a toxicity of a SARM compound, comprising attaching to an A ring or a B ring of said SARM one of the structures described above in the method of increasing bioavailability.
• the present invention provides a prodrug in which one of the parent SARM compounds is modified by adding an oxazolone, an isoxazolone, an oxazol, or an isoxazol, e.g. of the following structures:
• Chiral carbon refers, in one embodiment, to the carbon adjacent to the carbonyl carbon on the backbone of the SARM compound.
• the substituent R denotes, where not otherwise indicated, an alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 ; aryl, phenyl, F, CI, Br, I, alkenyl, or hydroxyl (OH).
• prodrug refers, in one embodiment, to a substance which can be converted in-vivo into a biologically active agent by such reactions as hydrolysis, esterification, desterification, activation, salt formation and the like.
• prodmg refeis to a derivative of a drug that exhibits an incieased aqueous solubility.
• prodrug refers to a derivative of a drag that exhibits a deci eased aqueous solubility.
• prodmg refers to a deiivative of a drag that exhibits an increase bioavailability.
• prodrug refers to a derivative of a drag that exhibits a decreased toxicity
• p odmg refers to a derivative of a drag that exhibits an improved partitioning to a partic ⁇ lai body tissue or biological fluid.
• prodrug refeis to a derivative of a drug that exhibits altered pharmaceutical properties relative to the parent compound.
• prodiug refers to a derivative of a drug that exhibits an altered phaimacological property relative to the parent compound.
• the SARM compound from which the piodmg is derived is refe ⁇ ed to as a "parent SARM compound” or "pending compound.”
• prodrug refers to a derivative of a drug that exhibits an enhanced delivery characteristic relative to the parent compound.
• the enlianced delivery characteristic is an increased concentration in a target tissue.
• increased transport to a specific tissue occurs via a particular transport mechanism.
• the enlianced delivery characteristic is a decreased concentration in a non-target tissue.
• the prodmg modification prevents exposure of tissue where active drug could be absorbed into systemic cii dilation, tlirough limiting exposuie of that tissue to active drug.
• the piodrug is enzymatically activated by an enzyme (e.g. bioreductive enzymes or enzymes pievalent in hypoxic tissue such as DT diaphorase, NADPH reductase, xanthine dehydrogenase, etc),
• an enzyme e.g. bioreductive enzymes or enzymes pievalent in hypoxic tissue such as DT diaphorase, NADPH reductase, xanthine dehydrogenase, etc
• the piodrug is enzymatically activated in a target tissue by an tissue-specific oi disease-specific enzyme piesent therein (e.g. PSA, PSMA, bacterial or viral enzymes, etc ).
• the prodrug is enzymatically by an abzyme
• the prodmg modification minimizes fust pass metabolism.
• the prodmg modification masks an organoleptic property of the parent compound.
• the prodrug modification enlianced an other formulation attribute (e.g. a physicochemical property for analytical reasons, foi mulations or manufacturing reasons, etc.).
• the prodmg modification confers upon the pended compound a specific pha ⁇ nacokinetic property.
• the propeity is an extended release
• the property is a compatibility with a route of administration
• the property is an absorption phase.
• prodmg refers to any other definition of "prodrug” known in the art. Each definition represents a separate embodiment of the present invention.
• alkyl group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons, The alkyl group may be unsubstituted or substituted by one or more groups selected from halogen (e.g.
• haloalkyl refers to an alkyl group as defined above, which is substituted by one oi moie halogen atoms, e.g. by F, CI, Br or I.
• a "halogen” refers to elements of Group VII or the periodic table, e g. F, CI, Br or I.
• an "aiyl” group refeis to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen (e.g F, CI, Br, I), haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, caiboxy or thio or thioalkyl.
• halogen e.g F, CI, Br, I
• Nonlimiting examples of aiyl rings are phenyl, naphthyl, pyianyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyiidinyl, fuianyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
• a "hydroxyl” group lefers to an OH group.
• An “alkenyl” group lefers to a group having at least one carbon to carbon double bond
• arylalkyl lefers to an alkyl bound to an aryl, wherein alkyl and aryl aie as defined above.
• An example of an aralkyl group is a benzyl group.
• the invention ielates to the use of an analog of the piodrug, In another embodiment, the invention ielates to the use of a derivative thereof In anothei embodiment, the invention ielates to the use of an isomei thereof. In another embodiment, the invention relates to the use of a metabolite theieof. In another embodiment, the invention relates to the use of a pharmaceutically acceptable salt thereof In another embodiment, the invention relates to the use of a pharmaceutical product thereof In anothei embodiment, the invention relates to the use of a hydrate theieof.
• the invention relates to the use of an N-oxide theieof
• the invention ielates to the use of a polymoiph thereof.
• the invention relates to the use of a crystal thereof.
• the invention relates to the use of any of a combination of an analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, oi N-oxide, polymorph oi crystal of the SARM compounds of the piesent invention,
• the te ⁇ n “isomer” includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conforrnational isomeis and analogs, and the like
• this invention encompasses the use of various optical isomeis of the SARM prodrugs. It will be appreciated by those skilled in the art that the SARM prodrugs of the piesent invention contain at least one chiial center. Accordingly, the SARM prodiugs used in the methods of the present invention may exist in, and be isolated in, optically-active or lacemic forms, Some prodiugs may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or steieroisomeiic form, or mixtures thereof, which form possesses properties useful in the methods as described herein.
• the SARM prodiugs are the pure (R)-isomers, In another embodiment, the SARM prodrugs are the pine (S)-isomers In another embodiment, the SARM prodiugs are a mixtuie of the (R) and the (S) isomeis. In another embodiment, the SARM prodrugs are a lacemic mixtuie comprising an equal amount of the (R) and the (S) isomeis, It is well known in the art how to prepare optically-active forms (for example, by lesolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiial stationary phase).
• the invention includes phaimaceutically acceptable salts of amino-substituted prodrugs with oiganic and inorganic acids, for example, citric acid and hydrochloric acid
• the invention also includes N-oxides of the amino substituents of the prodrugs described heiein.
• Pha ⁇ naceutically acceptable salts can also be prepared from the phenolic prodiugs by treatment with inorganic bases, for example, sodium hydroxide
• esters of the phenolic prodrugs can be made with aliphatic and aromatic carboxylic acids, for example, acetic acid and benzoic acid esters.
• This invention further includes derivatives of the SARM prodiugs.
• derivatives includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and tire like
• this invention further includes hydrates of the SARM prodrugs.
• teim "hydiate” includes but is not limited to hemihydrate, monohydrate, dihydiate, trihydrate and the like.
• furihei includes metabolites of the SARM prodrugs.
• the teim "metabolite” means any substance produced from anotlier substance by metabolism oi a metabolic process,
• This invention further includes pharmaceutical products of the SARM prodrugs
• pharmaceutical product means a composition suitable for pha ⁇ naceutical use (pharmaceutical composition), as defined heiein.
• This invention further includes crystals of the SARM prodiugs
• this invention provides polymorphs of the SARM prodiugs.
• crystal means a substance in a crystalline state.
• polymorph refers to a particular crystalline state of a substance, having particulai physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
• Suitable when describing an atom, refers, in one embodiment, lo an atom with appropriate leactivity to bind at the indicated location. In anothei embodiment, “suitable” refers to a sterically accessible atom. In another embodiment, “suitable” refeis to an atom which can be conjugated without compromising an biological activity (e.g.
• SARM compounds are a novel class of androgen receptoi targeting agents, that have been shown to be useful for a) male contraception; b) treatment of a variety of hoimone-related conditions, for example conditions associated with Androgen Decline in Aging Male (ADAM), such as fatigue, depression, decreased libido, sexual dysfunction, erectile dysfunction, hypogonadism, osteoporosis, hair loss, anemia, obesity, sarcopenia, osteopenia, osteoporosis, benign prostate hyperplasia, alterations in mood and cognition and prostate cancet; c) treatment of conditions associated with Androgen Decline in Female (ADIF), such as sexual dysfunction
• This section describes properties of the pended SARM compounds from which prodiugs aie derived
• the prodrugs are designed, in one embodiment, to be biologically piocessed to yield the pended SARM compound, or another SARM compound with AR binding activity, in the subject
• receptors foi extiacellular signaling molecules are collectively refe ⁇ ed to as "cell signaling receptors"
• Many cell signaling receptors are tiansmembrane proteins on a cell surface; when they bind an extracellular signaling molecule (i e,, a ligand), they become activated so as to geneiate a cascade of intracellulai signals that alter the behavior of the cell
• the leceplors aie inside the cell and the signaling ligand has to enter the cell to activate them; these signaling molecules therefore must be sufficiently small and hydrophobic to diffuse across the plasma membrane of the cell
• Steroid hormones are one example of small hydrophobic molecules that diffuse diiectly across the plasma membiane of target cells and bind to intracellular cell signaling leceptors
• These receptors are structurally related and constitute the inhacellulai receptor superfamily (or steroid-hormone receptor supeifamily)
• Steroid ho ⁇ none receptors include progesterone receptors, estrogen receptors, androgen leceptors, glueocorticoid receptors, and mineralocorticoid receptois.
• the piesent invention is particulaily directed to androgen receptors
• the leceptors can be blocked to prevent ligand binding
• affinity the affinity of a substance is gieater than the original hoimone, it will compete with the hoimone and bind the binding site more frequently.
• signals may be sent through the receptoi into the cell, causing the cell to respond in some fashion This is called activation. On activation, the activated receptor then directly legulates the transcription of specific genes.
• the substance and the receptoi may have certain attributes, other than affinity, in ordei to activate the cell Chemical bonds between atoms of the substance and the atoms of the receptors may form In some cases, this leads to a change in the configuration of the receptor, which is enough to begin the activation process (called signal transduction).
• the present invention is directed to prodrugs of SARM compounds that are agonist compounds
• a receptoi agonist is a substance which binds receptois and activates them.
• the SARM compounds of the present invention are useful in binding to and activating steroidal hoimone leceptois
• the agonist compounds of the piesent invention is an agonist which binds the androgen receptor
• the compounds has high affinity for the androgen receptor.
• the agonist also has anabolic activity.
• the piesent invenhon provides prodiugs of SARM compounds that have agonistic and anabolic activity of a nonsteioidal compounds foi the androgen receptor
• the present invention is directed to prodiugs of SARM compounds that are antagonist compounds.
• a ieceptor antagonist is a substance which binds receptois and inactivates them.
• the SARM compounds of the piesent invention bind and inactivate steroidal hormone receptors.
• the antagonist compounds of the piesent invention is an antagonist which binds the androgen receptor.
• the compounds has high affinity for the androgen ieceptor.
• the parent SARM compounds of the present invention can be classified as partial AR agonist/antagonists.
• the SARMs are AR agonists in some tissues, to cause increased transcription of AR-responsive genes (e.g, muscle anabolic effect). In other tissues, these compounds seive as inhibitors at the AR to prevent agonistic effects of the native androgens.
• AR agonistic activity can be deteimined by monitoring the ability of the SARM compounds to maintain and/or stimulate the growth of AR containing tissue such as prostate and seminal vesicles, as measured by weight
• AR antagonistic activity can be deteimined by monitoring the ability of the parent SARM compounds to inhibit the growth of AR containing tissue
• SARM compounds stimulate the AR and have selective anabolic and, in some cases, androgenic activity.
• administration of SARM prodiugs that are converted in the subject to SARM compounds is an effective strategy foi heating conditions disclosed herein.
• the compounds of the present invention bind either reversibly or irreversibly to an AR,
• the AR is an AR of a mammal
• the AR is an AR of a human.
• the SARM compounds bind reversibly to the AR of a mammal, for example a human.
• Reversible binding of a compound to a receptoi means, in one embodiment, that the compound can detach fiom hie ieceptor after binding.
• the SARM compounds bind iireveisibly to the androgen receptor of a mammal, for example a human.
• the compounds of the present invention may contain a functional group (e g affinity label) that allows alkylation of the androgen receptor (i.e covalent bond formation)
• a functional group e g affinity label
• the SARM compounds are alkylating agents that bind irreversibly to the leceptoi and, accordingly, cannot be displaced by a steroid, such as the endogenous ligands DHT and testosterone.
• alkylating agent is defined heiein as an agent that alkylates (foims a covalent bond) with a cellular component, such as DNA, RNA or enzyme It is a highly reactive chemical that introduces alkyl radicals into biologically active molecules and thereby pi events their proper functioning
• the alkylating moiety is an elechophilic group that interacts with nucleophilic moieties in cellulai components.
• a method is provided foi binding the SARM compounds of the piesent invention to an androgen leceptoi by contacting the ieceptor with a SARM piodmg and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, polymorph, ciystal or any combination thereof, under conditions effective to cause the SARM compounds to bind the androgen ieceptor.
• the binding of the SARM compounds to the androgen receptor enables the prodiugs of the present invention to be useful as a male contraceptive and in a numbei of hormone therapies
• the agonist compounds bind to and activate the androgen receptor
• the antagonist compounds bind to and inactivate the androgen ieceptor.
• Andiogen-dependent conditions which may be treated according to the piesent invention include those conditions which are associated with aging, such as hypogonadism, sarcopenia, eiythropoiesis, osteoporosis, and any other conditions detennined to be dependent upon low androgen (e.g., testosterone) levels.
• hie present invention provides a a method of inducing apoptosis in a cancer cell, comprising hie step of contacting the cell with with the selective androgen leceptoi modulator compound of the present invention and/or its analog, derivative, isomei, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N-oxide, prodmg, polymorph, crystal or any combination thereof, in an amount effective to induce apoptosis in said cancer cell.
• contacting means that the SARM compound of the piesent invention is introduced into a sample containing hie enzyme in a test tube, flask, tissue cultureor CHip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of hie SARM to hie enzyme.
• Methods for contacting the samples with the SARM or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be mn. Incubation methods are also standard and aie known to those skilled in the art.
• the term "contacting" means that hie SARM compound of the present invention is introduced into a subject ieceiving treatment, and the SARM compound is allowed to come in contact with the androgen receptor in vivo.
• Ostoporosis refers, in one embodiment, to a thinning of the bones with reduction in bone mass due to depletion of calcium and bone protein.
• osteoporosis pases a person to fractures, which are often slow to heal and heal poorly. Unchecked osteoporosis can lead to changes in posture, physical abnormality, and decreased mobility.
• BPH benign prostate hyperplasia
• BPH benign prostate hyperplasia
• proliferative abnormality found in any internal organ and the major cause of morbidity in the adult male.
• BPH occurs in over 75% of men over 50 years of age, reaching 88% prevalence by the ninth decade.
• BPH frequently results in a gradual squeezing of the portion of the urethra which traverses the prostate (prostatic urethra). This causes patients to experience a frequent uige to urinate because of incomplete emptying of the bladder and uigency of urination.
• the obstruction of urinary flow can also lead to a general lack of control over urination, including difficulty initiating urination when desired, as well as difficulty in preventing urinary flow because of the inability to empty urine from the bladdei, a condition known as overflow urinary incontinence, which can lead to urinary obstruction and to urinary failure.
• depression refers to an illness that involves the body, mood and thoughts, that affects the way a person eats, sleeps and the way one feels about oneself, and thinks about things.
• the signs and symptoms of depression include loss of interest in activities, loss of appetite oi overeating, loss of emotional expression, an empty mood, feelings of hopelessness, pessimism, guilt oi helplessness, social withdrawal, fatigue, sleep disturbances, trouble concentrating, remembering, or making decisions, restlessness, iiritability, headaches, digestive disorders or chronic pain
• hair loss medically known as alopecia, refers, in one embodiment, a common type of male-pattern baldness. Baldness typically begins with patch hair loss on the scalp and sometimes progresses to complete baldness and even loss of body hah Hair loss affects both males and females,
• Anemia is caused by four basic factors: a) hemorrhage (bleeding); b) hemolysis (excessive destruction of red blood cells); c) underproduction of red blood cells; and d) not enough normal hemoglobin
• anemia including aplastic anemia, benzene poisoning, Fanconi anemia, hemolytic disease of the newborn, hereditary spherocytosis, iron deficiency anemia, osteopetrosis, pernicious anemia, sickle cell disease, thalassemia, rnyelodysplastic syndrome, and a variety of bone marrow diseases.
• the SARM compounds of the present invention are useful in pieventing and/oi heating any one oi more of the above-listed forms of anemia.
• "Obesity" lefers to the state of being well above one's normal weight.
• Obesity is defined, in another embodiment, as having a Body to Mass Index (BMI) of 30 or above Obesity is often multifactoiial, based on both genetic and behavioral factois Oveiweight due to obesity is a significant contributor to health problems It incieases the risk of developing a numbei of diseases including: Type 2 (adult-onset) diabetes; high blood pressure (hypertension); stroke (cerebiovascular accident or CVA); heart attack (myocardial infarction oi MI); heart failure (congestive heart failuie); cancer (certain fo ⁇ ns such as cancer of the prostate and cancer of the colon and lectum); gallstones and gallbladdei disease (cholecystitis); Gout and gouty arthritis; osteoarthritis (degenerative arthritis) of the knees, hips, and the lower back; sleep ap ea (failuie to breath normally during sleep
• BMI Body to Mass Index
• the term "obesity" includes any one of the above-listed obesity-i elated conditions and diseases
• the prodiugs of SARM compounds of the piesent invention are useful in preventing and/or treating obesity and any one or more of the above-listed obesity-related conditions and diseases
• the SARM compounds of the present invention are, in one embodiment, a novel class of AR taigeting agents that demonstrate androgenic or anti-androgenic and anabolic activity. In another embodiment, the SARM compounds of the present invention are a novel class of non-steroidal ligands foi the AR.
• the SARM compounds of the present invention may be categorized into subgroups depending on their biological activity. For example, several SARM compounds have an agonistic effect on muscle oi bone, whereas otheis have an antagonistic effect.
• the AR is a ligand-activated hanscriptional regulatory protein that mediates induction of male sexual development and function tlirough its activity with endogenous androgens (male sex hormones)
• the androgens e g DHT and testosterone
• aie steroids that are produced in the body by hie testis and the cortex of the adrenal gland.
• SARMS are AR ligands that differ from pieviously known AR ligands in that SARMS aie non-steioidal.
• a receptor agonist is, in one embodiment, a substance that binds a receptor and activates it
• a ieceptor partial agonist is, in one embodiment, a substance that binds a receptor and partially activates it.
• a receptor antagonist is, in one embodiment, a substance that binds a ieceptor and inactivates it.
• the SARM compounds of the present invention have a tissue-selective effect, wheiein one agent may be an agonist, partial agonist and/or antagonist, depending on the tissue.
• the SARM compound may stimulate muscle tissue and at the same time inhibit prostate tissue.
• the SARMs of the present invention are AR agonists.
• AR agonistic activity can be deteimined by monitoring hie ability of the SARM compounds to maintain and/or stimulate the growth of AR containing tissue such as prostate and seminal vesicles, as measured by weight AR antagonistic activity can be determined by monitoring the ability of the SARM compounds inhibit the growth of AR containing tissue.
• the SARM compounds of the present invention can be classified as partial AR agonist/antagonists
• the SARMs are AR agonists in some tissues, causing incieased transcription of AR-responsive genes (e.g muscle anabolic effect). In othei tissues, these compounds serve as competitive inhibitors of testosterone and/oi dihydrotestosterone (DHT) on the AR to prevent agonistic effects of the native androgens.
• DHT dihydrotestosterone
• the SARM compounds of hie present invention bind leversibly to the AR.
• the SARM compounds bind i ⁇ eveisibly to the AR.
• the compounds of the present invention may, in one embodiment, contain a functional group (affinity label) that allows alkylation of the AR (i.e covalent bond formation)
• a functional group affinity label
• the compounds bind irreversibly to the receptoi and, accordingly, cannot be displaced by a steroid, such as the endogenous ligands DHT and testosterone.
• the SARM compound is administered to the subject.
• an analogue of the SARM is administered in anothei embodiment, a derivative of the SARM is administered.
• an isomer of the SARM is administered.
• a metabolite of the SARM is administered in another embodiment, a phaimaceutically acceptable salt of the SARM is administered.
• a pharmaceutical product of the SARM is administered.
• a hydrate of the SARM is administeied.
• an N-oxide of the SARM is administeied.
• the methods of the piesent invention comprise administering any of a combination of an analogue, deiivative, isomer, metabolite, phaimaceutically acceptable salt, pharmaceutical product, hydrate or N-oxide of the SARM.
• isomei iefers, in one embodiment, an optical isomer. In another embodiment, “isomei” refers to an analog. In another embodiment, “isomei” refers to a structural isomei. In anothei embodiment, “isomei” iefers to a structural analog. In anothei embodiment, “isomer” refers to a confbrmational isomer. In another embodiment, “isomer” iefers to a confoimational analog. In anottier embodiment, "isomei" iefers to any other type of isomer known in the art. Each type of isomei iepresents a separate embodiment of the present invention.
• this invention encompasses the use of various optical isomers of the SARM compound.
• the SARMs of the present invention contain at least one chiral center.
• the SARMs used in the methods of the piesent invention may exist in, and be isolated in, optically active or racemic forms. Some compounds may also exhibit polymorphism. It is to be undei stood that the present invention encompasses any racemic, optically active, polymorphic, or stereroisomeric foi , or mixtuies thereof, which form possesses properties useful in the treatment of androgen-ielated conditions described herein.
• the SARMs are the pure (R)-isomers
• the S/VRMs are the pure (S)-isome ⁇ s
• the SARMs are a mixture of the (R) and (S) isomers.
• hie SARMs are a racemic mixture comprising an equal amount of the (R) and (S) isomers It is well known in the art how to prepare optically-active foi s (foi example, by resolution of hie racemic form by lecrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
• the invention includes, in anohier embodiment, phaimaceutically acceptable salts of ami no-substituted compounds with organic and inorganic acids, foi example, citric acid and hydrochloric acid.
• the invention also includes N-oxides of the amino substituents of the compounds described herein.
• Pharmaceutically acceptable salts can also be piepared from the phenolic compounds by treatment with inorganic bases, foi example, sodium hydroxide
• esters of the phenolic compounds can be made with aliphatic and aromatic caiboxylic acids, for example, acetic acid and benzoic acid esteis
• This invention fuither includes, in another embodiment, derivatives of the SARM compounds.
• derivatives includes but is not limited to ethei derivatives, acid derivatives, amide derivatives, ester derivatives and the like
• furthei includes hydrates of the SARM compounds
• hydrate includes but is not limited to hemi-hydrate, monohydiate, dihydrate, trihydrate and the like.
• This invention furthei includes, in another embodiment, metabolites of the SARM compounds.
• the term "metabolite” iefers, in one embodiment, to any substance produced from another substance by metabolism or a metabolic process
• This invention further includes, in one embodiment, pharmaceutical products of the SARM compounds.
• pharmaceutical product refers, in one embodiment, to a composition suitable for phamiaceutical use (phaimaceutical composition), as defined heiein 00186]
• the SARM compound of the present invention is a compound repiesented by the structure of formula I:
• G is O or S;
• X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
• T is OH, OR, -NHCOCH 3 , or NHCOR;
• Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
• Y is CF 3 , F, I, Br, CI, CN, CR 3 or SnR 3 ;
• Q is alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OS0 2 R, S0 2 R, SR, SCN, NCS, OCN, or NCO; or Q together with the benzene
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH CH 3 , or CF 2 CF 3 .
• the SARM compound of the present invention is lepresented by the structuie of foimula (II),
• X is a bond, O, CH 2 , NH, Se, PR, NO oi NR; Z is N0 2 , CN, COOH, COR, NHCOR or CONHR; Y is CF 3 , F, I, Br, CI, CN, CR 3 or SnR 3 ; Q is alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3s NR 2 , NHCOCH 3 , NHCOCF 3s NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, S0 2 R, SR, SCN, NCS, OCN, or NCO; 01 Q together with the benzene ring to which it is attached is a fused ring system lepresented by stmcture A, B or C;
• a B and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CFIF 2 , CF 3 , CF 2 CF3, aiyl, phenyl, F, I, Bi, CI, alkenyl or OH.
• the SARM compound is a compound of formula II wherein X is O
• the SARM compound is a compound of formula II wherein Z is NO 2 .
• the SARM compound is a compound of foimula II wherein Z is CN.
• the SARM compound is a compound of formula II wherein Y is CF 3 .
• the SARM compound is a compound of formula II wherein Q is NHCOCH 3
• the SARM compound is a compound of formula II wherein Q is F
• the substituent R in the compound of foimula II is an alkyl group
• the substituent R is a haloalkyl gioup.
• the substituent R is a dihaloalkyl group.
• the substituent R is a trihaloalkyl group.
• the substituent R is a CFLF moiety.
• the substituent R is a CHF 2 moiety.
• the substituent R is a CF 3 moiety.
• the substituent R is a CF 2 CF 3 moiety.
• the substituent R is an aryl group.
• the substituent R is a phenyl group In anothei embodiment, the substituent R is F. In another embodiment, the substituent R is I, In another embodiment, the substituent R is a Br. In another embodiment, the substituent R is CI. In another embodiment, the substituent R is an alkenyl group In another embodiment, the substituent R is an OH moiety.
• Each substituent represents a separate embodiment of the present invention.
• the SARM compound of hie present invention is a compound lepresented by the schedulechire of formula III:
• Z is N0 2 , CN, COR, or CONHR; and Y is I, CF 3 , Br, CI, or SnR 3 .
• Z in compound (III) is NOi.
• Z in compound (III) is CN.
• Y in compound (II) is CF 3 .
• Q in compound (III) is CN.
• the SARM compound is a compound represented by a structuie of formula IV:
• hie SARM compound of hie present invention is a compound repiesented by the stracture of formula V:
• X is a bond, O, CH 2 , NH, Se, PR, NO or NR;
• G is O oi S;
• R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH2CH3, 01 CF 2 CF 3 ;
• T is OH, OR, -NHCOCH3, 01 NHCOR;
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, F, I, Br, CI, alkenyl or OH;
• A is a ring selected from:
• B is a ring selected from: wherein A and B aie not simultaneously a benzene ring; Z is N0 2 , CN, COOH, COR, NHCOR or CONHR; Y is CF 3 , F, I, Br, CI, CN, CR 3 or SnR 3 ; Qi and Q 2 are independently of each other a hydrogen, alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CFI3, NHSOzR, OR, COR, OCOR, OS0 2 R, S0 2 R, SR, SCN, NCS, OCN, NCO,
• Q 3 and Q aie independently of each other a hydrogen, alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF3, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, HCSCH 3 , HCSCF3, NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR, OCOR, OS0 2 R, S0 2 R, SR, SCN, NCS, OCN, or NCO; Wi is O, NH, NR, NO or S; and W 2 is N or NO,
• the SARM compound is a compound of foimula V wherein X is O, In another embodiment, the SARM compound is a compound of formula V wherein G is O. In another embodiment, the SARM compound is a compound of formula V wherein T is OH. In another embodiment, the SARM compound is a compound of foimula V wherein R 1 is CFI 3 . In another embodiment, the SARM compound is a compound of formula V wherein Z is N0 2 - In anothei embodiment, the SARM compound is a compound of formula V wherein Z is CN.
• the SARM compound is a compound of formula V wherein Y is CF 3
• the SARM compound is a compound of foimula V wheiein Q ⁇ is NHCOCH 3
• the SARM compound is a compound of formula V wherein Qj is F.
• the substituents Z and Y can be, in one embodiment, in any position of hie ring cairying these substituents (heieinafter "A ring").
• the substituent Z is in the para position of the A ring
• the substituent Y is in the meta position of the A ring.
• the substituent Z is in the paia position of the A ring and substituent Y is in the meta position of the A ring.
• the substituents Qi and Q 2 can be, in one embodiment, in any position of the ring cairying these substituents (heieinafter "B ring").
• the substituted Qi is in hie paia position of the B ring.
• the subsituent is Q 2 is H
• the substitutent Q ⁇ is in the para position of the B ring and the subsituent is Q 2 is H.
• the substitutent Qi is NHCOCH 3 and is in the paia position of the B ring, and the substituent is Q 2 is H
• each substituent of each of hie above variables represents a separate embodiment of the present invention Further, each position enumerated above of each of the above substituents lepresents a separate embodiment of the present invention.
• the SARM compound of the present invention is a compound lepresented by the structure of formula VI:
• X is a bond, O, CH 2 , NH, Se, PR, NO or NR; G is 0 or S; T is OH, OR, -NHCOCH 3 , or NHCOR; R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF2CF 3 , aryl, phenyl, F, I, Br, CI, alkenyl or OH; R 1 is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ; R 2 is F, CI, Br, I, CH 3 , CF 3 , OFI, CN, N0 2 , NFICOCH3, NHCOCF 3 , NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, NR 2 , SR, SCN, NCS, OCN, NCO
• Z is N0 2 , CN, COR, COOH, or CONHR;
• Y is CF 3 , F, Br, CI, I, CN, or SnR 3 ;
• Q is H, alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , S11R 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHS0 2 CH 3 , NHS0 2 R, OH, OR, COR, OCOR, OS0 2 R, S0 2 R, or SR; or Q together with the benzene ring to which it is attached is a fused ring system represented by stmcture A, B or C:
• the SARM compound is a compound of foimula VI wheiein X is O.
• the SARM compound is a compound of formula VI wherein G is O,
• the SARM compound is a compound of foimula VI wheiein Z is NO 2 .
• the SARM compound is a compound of foraiula VI wherein Z is CN
• the SARM compound is a compound of fomuila VI wherein Y is CF 3
• the SARM compound is a compound of foimula VI wheiein Q is NHCOCH 3 .
• the SARM compound is a compound of fonnula VI wheiein Q is F
• the SARM compound is a compound of fonnula VI wheiein T is OH.
• the SARM compound is a compound of foimula VI wheiein Ri is CH 3 .
• the SARM compound is a compound of formula VI wherein Q is F and R 2 is CH 3
• the SARM compound is a compound of foimula VI wheiein Q is F and R 2 is CI
• the substituents Z, Y, and R 3 can be, in one embodiment, in any position of the ring carrying these substituents (heieinafter "A ring").
• the substituent Z is in the para position of the A ring.
• the substituent Y is in the meta position of the A ring.
• the substituent Z is in the para position of the A ring and substihient Y is in hie meta position of the A ring.
• the substituents Q and R 2 can be, in one embodiment, in any position of the ring carrying these substituents (hereinafter "B ring")
• the substitutent Q is in the paia position of the B ring.
• the substitutent Q is in the para position of the B ring.
• the substitutent Q is NHCOCH 3 and is in the paia position of the B ring
• each substituent of each of the above variables represents a separate embodiment of the piesent invention. Further, each position enumerated above of each of the above substituents repiesents a separate embodiment of the present invention. Further, each number enumerated above of each of the above integers represents a separate embodiment of the piesent invention.
• the SARM compound of the present invention is a compound repiesented by the stmcture of fonnula VII:
• R 2 is F, CI, Br, I, CH 3 , CF 3 , OH, CN, N0 2 , NHCOCH3, NHCOCF3, NHCOR, alkyl, aiylalkyl, OR, NFI 2 , NHR, NR 2 , or SR;
• R 3 is F, CI, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 , or SnR 3 ; 01 R 3 together with the benzene ring to which it is attached forms a fused ring system lepresented by the structure:
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aiyl, phenyl, F, I, Br, CI, alkenyl or OFI;
• Z is N0 2 , CN, COR, COOH, or CONHR;
• Y is CF 3l F, Br, CI, I, CN, or S11R3;
• Q is H, alkyl, F, I, Br, CI, CF 3; CN, CR 3 , SnR 3 , NR 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH3, NHCSCF3, NHCSR, NHSO2CH3, NHSO 2 R, OH, OR, COR, OCOR, OSO2R, S0 2 R, or SR; 01 Q
• a n is an integer of 1-4; and m is an integei of 1 -3
• the SARM is a compound of foimula VII wheiein Z is NO .
• the SARM is a compound of formula VII wherein Z is CN
• the SARM is a compound of formula VII wherein Y is CF 3
• the SARM is a compound of foimula VII wherein Q is NHCOCH 3
• the SARM is a compound of foimula VII wheiein Q is F
• the SARM is a compound of formula VII wheiein Q is F and R 2 is CH 3
• the SARM is a compound of foimula VII wheiein Q is F and R 2 is CI.
• the substituents Z, Y and R 3 can be in, in one embodiment, any position of the A ring, and the substituents Q and R 2 can be, in one embodiment, in any position of B ring, as described above for compound VI. Furthermore, as discussed above, when the integers m and n are greater than one, the substituents R 2 and R 3 are not limited to one particular substituent, and can be any combination of the substituents listed above
• each substituent of each of the above variables repiesents a separate embodiment of the present invention. Further, each position enumerated above of each of the above substituents represents a separate embodiment of the present invention Further, each number enumerated above of each of the above integers lepiesents a sepaiate embodiment of the present invention.
• the SARM compound of the present invention is a compound represented by the structure of formula VIII.
• the SARM compound of the present invention is a compound represented by the stracture of formula IX.
• the SARM compound of the present invenhon is a compound represented by the structure of foimula X. NHCOCH 3
• the SARM compound of the present invention is a compound repiesented by the structure of formula XI.
• the SARM compound of the present invention is a compound represented by the schedule of foimula XII.
• the SARM compound of the piesent invention is a compound represented by the stracture of foimula XIII
• the SARM compound is a compound represented by a structure of fonnula XIV:
• p is 2, In another embodiment, p is 3. In another embodiment, p is 4. In another embodiment, p is 5, The lest of the substituents are as defined above for formula VI.
• the SARM compound is a compound represented by a structure of formula XV:
• the SARM compound is a compound represented by a structure of fonnula XVI:
• the SARM compound is a compound represented by a stmcture of formula XNII:
• p is 1. In one embodiment, p is 2 In anothei embodiment, p is 3. In another embodiment, p is 4, The rest of the substituents are as defined above for formula VII.
• the SARM compound is a compound represented by a stmcture of foimula XVIII:
• the SARM is a compound of formula XVIII wheiein Q is aceta ido (NHCOCH )
• the SARM is a compound of formula XVIII wherein Q is trifiuoioacetamido (NHCOCF 3 ),
• the SARM is a compound of foimula XVIII wherein Z is NO 2 .
• the SARM is a compound of fonnula XVIII wherein Z is CN.
• the SARM is a compound of foimula XVIII wherein Z is COR.
• the SARM is a compound of formula XVIII wherein Z is CONHR
• the SARM is a compound of formula XVIII wherein Y is CF 3 .
• the SARM is a compound of formula XVIII wheiein Y is I.
• the SARM is a compound of formula XVIII wherein Y is Br.
• the SARM is a compound of foimula XVIII wherein Y is CI
• the SARM is a compound of foimula XVIII wherein Y is SnR 3 .
• the SARM is a compound of formula XVIII wherein R is an alkyl group. In another embodiment, the SARM is a compound of formula XVIII wherein R is OH. [000225]Each substituent of each of the above variables represents a separate embodiment of the present invention. Further, each position enumerated above of each of the above substituents represents a separate embodiment of hie present invention
• the SARM compound is a compound represented by a structure of foimula XIX:
• X is O, CH 2 , NH, Se, PR, NO orNR; T is OH, OR, -NHCOCH 3 , or NHCOR; Z is N0 2 , CN, COOH, COR, NHCOR or CONHR; Y is CF 3 , F, I, Bi, CI, CN, CR 3 or SnR 3 ; Q is alkyl, F, I, Br, CI, CF 3 , CN, CR 3 , SnR 3 , NR 2 , NHCOCH3, NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCFI3, NHCSCF 3 , NHCSR, NHSO2CH 3 , NHS0 2 R, OR, COR, OCOR, OS0 2 R, S0 2 R, or SR; or Q togethei with the benzene ring to which it is attached is a fused ring system represented by stmcture A,
• R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF2CF 3 , aryl, phenyl, F, I, Br, CI, alkenyl or OH; and R 1 is CH 3 , CH 2 F, CHF 2> CF3, CH 2 CH 3 , or CF 2 CF 3 .
• each substituent of each of the above variables represents a separate embodiment of the piesent invention. Further, each position enumerated above of each of the above substituents represents a separate embodiment of the present invention.
• the SARM compound is a compound of one of the above formulas wheiein X is O, In another embodiment, the SARM compound is a compound of one of the above formulas wherein X is a bond. In another embodiment, the SARM compound is a compound of one of the above formulas wheiein X is CH 2 . In another embodiment, hie SARM compound is a compound of one of the above formulas wherein X is NH, In another embodiment, the SARM compound is a compound of one of the above fo ⁇ nulas wherein X is Se. In another embodiment, the SARM compound is a compound of one of the above formulas wherein X is PR. In another embodiment, the SARM compound is a compound of one of the above formulas wherein X is NO. In another embodiment, the SARM compound is a compound of one of the above formulas wherein X is NR.
• the SARM compound is a compound of one of the above foimulas wheiein G is O. In another embodiment, the SARM compound is a compound of one of the above foimulas wherein G is S.
• the SARM compound is a compound of one of hie above formulas wherein T is OH. In another embodiment, the SARM compound is a compound of one of hie above formulas wherein T is OR. In another embodiment, the SARM compound is a compound of one of the above formulas wherein T is NHCOCH 3 . In another embodiment, hie SARM compound is a compound of one of the above fonnulas wherein T is NHCOR.
• the SARM compound is a compound of one of the above formulas wherein Z is N0 2 .
• the SARM compound is a compound of one of the above formulas wherein Z is CN
• the SARM compound is a compound of one of the above foimulas wherein Z is COOH.
• the SARM compound is a compound of one of the above formulas wherein Z is COR.
• the SARM compound is a compound of one of the above formulas wherein Z is NHCOR.
• the SARM compound is a compound of one of the above foimulas wherein Z is CONHR.
• the SARM compound is a compound of one of the above formulas wherein Y is CF 3 , In another embodiment, the SARM compound is a compound of one of the above foimulas wherein Y is F. In another embodiment, the SARM compound is a compound of one of the above foimulas wherein Y is I. In another embodiment, the SARM compound is a compound of one of the above foimulas wherein Y is Bi. In another embodiment, hie SARM compound is a compound of one of the above formulas wherein Y is CI. In another embodiment, the SARM compound is a compound of one of the above foimulas wherein Y is CN.
• the SARM compound is a compound of one of the above fo ⁇ nuias wheiein Y is CR 3 .
• the SARM compound is a compound of one of the above formulas wherein Y is SnR 3 -
• the SARM compound is a compound of one of the above fo ⁇ nulas wherein Q is NHCOCH 3 .
• the SARM compound is a compound of one of the above formulas wherein Q is F.
• the SARM compound is a compound of one of the above formulas wherein Q is alkyl.
• the SARM compound is a compound of one of the above formulas wherein Q is I.
• the SARM compound is a compound of one of the above formulas wherein Q is Br.
• the SARM compound is a compound of one of the above formulas wheiein Q is CI.
• the SARM compound is a compound of one of the above foimulas wherein Q is CF 3 . In another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is CN, In another embodiment, the SARM compound is a compound of one of hie above foimulas wherein Q is CR 3 . In another embodiment, the SARM compound is a compound of one of the above foimulas wherein Q is S11R 3 . In another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is NR 2 .
• the SARM compound is a compound of one of the above fo ⁇ ilas wherein Q is NHCOCF 3 In another embodiment, the SARM compound is a compound of one of the above foimulas wherein Q is NHCOR In another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is NHCONHR In another embodiment, the SARM compound is a compound of one of the above foimulas wherein Q is NHCOOR. In another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is OCONHR. In another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is CONHR.
• the SARM compound is a compound of one of the above formulas wherein Q is NFICSCH 3 In another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is NHCSCF 3 In anothei embodiment, the SARM compound is a compound of one of the above foimulas wheiein Q is NHCSR In anothei embodiment, the SARM compound is a compound of one of the above foimulas wherein Q is NHSO2CH3. hi another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is NFISOiR In anothei embodiment, the SARM compound is a compound of one of the above foimulas wherein Q is OR.
• the SARM compound is a compound of one of the above formulas wherein Q is COR In anothei embodiment, the SARM compound is a compound of one of the above formulas wherein Q is OCOR, In anothei embodiment, the SARM compound is a compound of one of the above foimulas wherein Q is OSO 2 R, In another embodiment, the SARM compound is a compound of one of the above fo ⁇ milas wheiein Q is S0 2 R. In anothei embodiment, the SARM compound is a compound of one of the above formulas wherein Q is SR. In anohier embodiment, the SARM compound is a compound of one of the above formulas wheiein Q is SCN.
• the SARM compound is a compound of one of the above formulas wherein Q is NCS. In anohier embodiment, the SARM compound is a compound of one of the above formulas wherein Q is OCN. In another embodiment, the SARM compound is a compound of one of the above formulas wherein Q is NCO. [000234]In another embodiment, the SARM compound is a compound of one of hie above fo ⁇ nulas wherein Q together with the benzene ring to which it is attached is a fused ring system represented by stmcture A, B or C:
• the SARM compound is a compound of one of the above foimulas wherein R is alkyl. In another embodiment, the SARM compound is a compound of one of the above foimulas wherein R is haloalkyl In another embodiment, the SARM compound is a compound of one of the above formulas wherein R is dihaloalkyl In anothei embodiment, the SARM compound is a compound of one of the above formulas wherein R is trihaloalkyl In another embodiment, the SARM compound is a compound of one of the above formulas wherein R is CH 2 F. In anothei embodiment, the SARM compound is a compound of one of the above formulas wherein R is CHF 2 .
• the SARM compound is a compound of one of the above formulas wherein R is CF 3 . In another embodiment, the SARM compound is a compound of one of the above formulas wherein R is CF 2 CF 3 . In another embodiment, the SARM compound is a compound of one of the above formulas wherein R is aiyl In anothei embodiment, the SARM compound is a compound of one of the above foimulas wherein R is phenyl In another embodiment, the SARM compound is a compound of one of the above foimulas wherein R is F.
• the SARM compound is a compound of one of the above foimulas wheiein R is I, In anothei embodiment, the SARM compound is a compound of one of the above fo ⁇ nulas wherein R is Bi. In anothei embodiment, the SARM compound is a compound of one of the above formulas wherein R is CI In anothei embodiment, the SARM compound is a compound of one of the above foimulas wherein R is alkenyl In anothei embodiment, the SARM compound is a compound of one of the above formulas wheiein R is OH
• the SARM compound is a compound of one of the above foimulas wherein R 1 is CH 3
• the SARM compound is a compound of one of the above fomiulas wherein R 1 is CH 2 F.
• the SARM compound is a compound of one of the above formulas wherein R 1 is CHF 2 .
• hie SARM compound is a compound of one of the above formulas wheiein R 1 is CF 3 -
• the SARM compound is a compound of one of the above formulas wherein R 1 is CH 2 CH 3 .
• the SARM compound is a compound of one of the above foimulas wherein R 1 is CF 2 CF 3 ,
• each substituent of each of X, Y, Z, G, T, Q, R and R 1 , for each of the above fo ⁇ nulas represents a separate embodiment of the present invention. Further, each position enumerated above of each of the above substituents repiesents a separate embodiment of the piesent invention. Furthei, each number enumerated above of each of the above integers repiesents a separate embodiment of the present invention.
• the SARM compound is a compound represented by a structure of fonnula XX:
• the SARM compound is a compound represented by a stmcture of formula XXI:
• the SARM compound is a compound represented by a structure of formula XXII:
• the SARM compound is a compound repiesented by a structuie of fonnula XXIII:
• the SARM compound is a compound represented by a structure of foimula XXIV:
• the SARM compound is a compound represented by a structure of foimula XXV:
• the SARM compound is a compound represented by a stmctuie of formula (XXVI): XXVI
• hie SARM compound is a compound represented by a structure of formula (XXVII):
• the SARM compound is a compound represented by a structuie of formula (XXVIII):
• the SARM compound is a compound represented by a spactuie of formula (XXIX):
• the SARM compound is a compound represented by a structure of formula (XXX):
• the SARM compound is a compound represented by a stmcture of formula (XXXI):
• the SARM compound is a compound represented by a structui e of fonnula (XXXII) :
• the SARM compound is a compound represented by a stmcture of formula (XXXIII):
• the SARM compound is a compound represented by a stmcture of foimula (XXXIV):
• the SARM compound is a compound represented by a structure of formula (XXXV):
• the SARM compound is a compound lepresented by a stracture of foimula (XXXVI):
• the SARM compound is a compound represented by a structure of formula (XXXVII):
• the SARM compound is a compound represented by a stmcture of fonnula (XXXVIII):
• the SARM compound is a compoimd represented by a structure of foimula (XXXIX):
• the SARM compound is a compound of fonnula XXIX wherein Q is F
• the SARM compound is a compound of formula XXIX wherein Q is CI.
• the SARM compound is a compound of formula XXIX wherein Q is Br.
• the SARM compound is a compound of formula XXIX wheiein Q is I.
• the SARM compound is a compound of formula XXIX wheiein Q is NHCOCH 3 .
• the SARM compound is a compound of formula XXIX wherein Q is NHCOCF 3 .
• the SARM compound is a compound of fonnula XXIX wherein Y is I, In another embodiment, the SARM compound is a compound of foimula XXIX wherein Y is CF 3 . In another embodiment, the SARM compound is a compound of formula XXIX wherein Y is Bi. In another embodiment, the SARM compound is a compound of foimula XXIX wherein Y is CI. In anothei embodiment, the SARM compound is a compound of formula XXIX wherein Y is SnR 3 . Each substituent of each of Y and Q for fonnula XXIX repiesents a separate embodiment of formula XXIX.
• the SARM compound is a compound represented by a structure of fonnula (XL):
• the SARM compound is a compound represented by a structure of fonnula (L):
• the SARM compound is a compound of formula L wheiein Q is F. In another embodiment, the SARM compound is a compound of foimula L wherein Q is CI. In another embodiment, the SARM compound is a compound of formula L wherein Q is Br. In another embodiment, hie SARM compound is a compound of fonnula L wheiein Q is I, In another embodiment, the SARM compound is a compound of formula L wherein Q is NHCOCFI 3 , In anothei embodiment, the SARM compound is a compound of formula L wherein Q is NHCOCF3
• the SARM compound is a compound of fonnula L wheiein Z is NO 2 In another embodiment, the SARM compound is a compound of formula L wheiein Z is CN. In another embodiment, the SARM compound is a compound of fonnula L wherein Z is COOH In anothei embodiment, the SARM compound is a compound of formula L wherein Z is COR In another embodiment, the SARM compound is a compound of foimula L wherein Z is NHCOR. In anothei embodiment, the SARM compound is a compound of foimula L wherein Z is CONHR. Each substituent of each of Z and Q for formula L repiesents a separate embodiment of foimula L.
• hie SARM compound is a compound represented by a structure of foimula (LI):
• the SARM compound is a compound of foimula LI wheiein Q is F In another embodiment, the SARM compound is a compound of foimula LI wherein Q is CI In another embodiment, the SARM compound is a compound of foimula LI wherein Q is Br. In anothei embodiment, the SARM compound is a compound of formula LI wherein Q is I. In another embodiment, the SARM compound is a compound of foimula LI wheiein Q is NHCOCH 3 . In another embodiment, the SARM compound is a compound of formula LI wheiein Q is NHCOCF 3 ,
• the SARM compound is a compound of formula LI wherein Y is I. In another embodiment, the SARM compound is a compound of formula LI wheiein Y is CF 3 . In another embodiment, the SARM compound is a compound of foimula LI wherein Y is Br. In another embodiment, the SARM compound is a compound of fonnula LI wherein Y is CI In anohier embodiment, the SARM compound is a compound of formula LI wherein Y is SnR 3 . Each substituent of each of Y and Q for' fonnula LI represents a separate embodiment of formula LI,
• the SARM compound is a compound represented by a structuie of fonnula (LII):
• the SARM compound is a compound of formula LII wherein Z is N0 2 .
• the SARM compound is a compound of formula LII wherein Z is CN.
• the SARM compound is a compound of fonnula LII wherein Z is COOH.
• the SARM compound is a compound of fonnula LII wherein Z is COR.
• the SARM compound is a compound of formula LII wherein Z is NHCOR.
• the SARM compound is a compound of formula LII wheiein Z is CONHR.
• Each substituent of each of Z and Q for formula LII represents a separate embodiment of formula LII,
• alkyl group refers, in one embodiment, to a saturated aliphatic hydrocarbon, including straight chain, branched-chain and cyclic alkyl groups, In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In anothei embodiment, the alkyl group has 1-4 carbons.
• the alkyl group may be unsubstituted or substituted by one oi more groups selected from F, 1, Br, CI, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, caiboxyl, thio and thioalkyl.
• alkenyl refers, in one embodiment, to an unsaturated hydrocarbon, including straight chain, branched chain and cyclic groups having one or more double bond.
• the alkenyl group may have one double bond, two double bonds, thiee double bonds etc Examples of alkenyl groups are ethenyl, propenyl, butenyl, cyclohexenyl etc
• the alkenyl group may be unsubstituted or substituted by one or more groups selected from F, I, Br, CI, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, caiboxyl, thio and thioalkyl
• haloalkyl group refers, in one embodiment, to an alkyl group as defined above, which is substituted by one or more halogen atoms, e,g. by F, CI, Br or I,
• an "aiyl” group refers, in one embodiment, to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from F, I, Br, CI, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl.
• Non-limiting examples of aiyl rings are phenyl, naphthyl, pyianyl, pynolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyi, thiazolyl, imidazolyl, isoxazolyl, and the like.
• a "hydroxyl” group refers, in one embodiment, to an OH group.
• An “alkenyl” group refers to a group having at least one carbon-carbon double bond.
• a halo group refers, in one embodiment, to F, CI, Br or I,
• an "aiylalkyl” group refeis, in one embodiment, to an alkyl bound to an aryl, wherein alkyl and aiyl are as defined above,
• An example of an arylalkyl group is a benzyl group.
• Pha ⁇ naceuticaI composition means, in one embodiment, a therapeutically effective amount of the active ingredient, i.e. the SARM compound, togethei with a phaimaceutically acceptable cairiei or diluent.
• a “therapeutically effective amount” refers, in one embodiment, to dial amount which provides a therapeutic effect foi a given condition and administration regimen.
• the phamiaceutical compositions containing the SARM agent can be administered to a subject by any method known to a peison skilled in the art, such as parentetally, paracancerally, transm ⁇ cosally, transdermally, intra-muscularly, intravenously, intra-deimally, subcutaneously, intra-peritonealy, intra-ventricularly, intra-cranially. inha-vaginally or intra-tumoially.
• the pharmaceutical compositions are administered orally, and are thus formulated in a fo ⁇ n suitable for oral administration, i.e. as a solid or a liquid preparation
• Suitable solid oral formulations include tablets, capsules, pills, granules, pellets and the like.
• Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like.
• the SARM compounds are formulated in a capsule
• the compositions of the present invention comprise in addition to the SARM active compound and hie inert carrier or diluent, a hard gelating capsule.
• the pharmaceutical compositions are administered by intravenous, intra-arterial, or inha-musculai injection of a liquid preparation.
• suitable liquid formulations include solutions, suspensions, dispersions, emulsions, oils and the like
• the pharmaceutical compositions are administered intravenously, and are thus formulated in a foim suitable for intravenous administration.
• the pharmaceutical compositions are administered intra-aiterially, and are thus formulated in a foim suitable for intia-arterial administration.
• the pharmaceutical compositions aie administered intra-muscularly, and are thus formulated in a form suitable for intra-musculai administration.
• the pharmaceutical compositions are administered topically to body surfaces, and are thus formulated in a foim suitable for topical administration.
• Suitable topical formulations include gels, ointments, creams, lotions, drops and the like Foi topical administration, the SARM agents or then physiologically tolerated derivatives such as salts, esters, N-oxides, and the like aie prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier,
• the pharmaceutical compositions are administered as a suppository, for example a rectal suppository or a urethral suppository Fuithei, in another embodiment, the phamiaceutical compositions are administered by subcutaneous implantation of a pellet.
• the pellet provides for controlled release of SARM agent over a period of time
• the active compound can be delivered in a vesicle, in particular a liposome (see Langei, Science 249:1527-1533 (1990); Treat et al , in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds ), Liss, New Yoik, pp, 353-365 (1989); Lopez-Berestein, ibid., pp 317-327; see generally ibid)
• carrier or diluent may be a solid carrier or diluent for solid formulations, a liquid cairiei oi diluent for liquid formulations, or mixtures thereof.
• Solid carrieis/diluents include, but are not limited to, a gum, a starch (e.g. com starch, pregeletanized starch), a sugar (e.g., lactose, mannitol, sucrose, dextrose), a cellulosic material (e.g. microcrystalline cellulose), an acrylate (e,g. polymethylacrylate), calcium caibonate, magnesium oxide, talc, or mixtures thereof.
• a starch e.g. com starch, pregeletanized starch
• a sugar e.g., lactose, mannitol, sucrose, dextrose
• a cellulosic material e.g. microcrystalline cellulose
• an acrylate e,g. polymethylacrylate
• phaimaceutically acceptable earners may be aqueous oi non-aqueous solutions, suspensions, emulsions or oils.
• non-aqueous solvents are propylene glycol, polyethylene glycol, and injectable organic esters such as ethyl oleate.
• Aqueous earners include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
• oils aie those of petroleum, animal, vegetable, or synthetic origin, foi example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-livei oil
• Parenter vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
• Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenisheis such as those based on Ringer's dexhose, and the like. Examples are sterile liquids such as watei and oils, with oi wihiout the addition of a suifactant and other phaimaceutically acceptable adjuvants.
• oils are those of petroleum, animal, vegetable, or synthetic origin, foi example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-livei oil,
• compositions may further comprise binders (e.g, acacia, cornstaich, gelatin, caibomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypiopyl methyl cellulose, povidone), disintegrating agents (e.g.
• binders e.g, acacia, cornstaich, gelatin, caibomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypiopyl methyl cellulose, povidone
• disintegrating agents e.g.
• buffers e.g., Tris-HCL, acetate, phosphate
• additives such as albumin or gelatin to prevent absoiption to surfaces
• delessnessents e.g., Tween 20, Tween 80, Pluionic F68, bile acid salts
• protease inhibitors e.g., Tween 20, Tween 80, Pluionic F68, bile acid salts
• surfactants e.g, sodium lauryl sulfate
• pe ⁇ neation enhancers solubihzing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e g.
• viscosity increasing agents e.g carbomei, colloidal silicon dioxide, ethyl cellulose, guar gum
• sweetners e.g, aspartame, citric acid
• preservatives e.g., Thimerosal, benzyl alcohol, paiabens
• lubricants e.g stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate
• flow-aids e.g. colloidal silicon dioxide
• plasticizers e.g.
• diethyl phthalate, triethyl citrate emulsifiers (e.g carbomei, hydroxypropyl cellulose, sodium lauryl sulfate), poiymei coatings (e g , poloxamers or poloxamines), coating and film forming agents (e.g. ethyl cellulose, acrylates, polymethaciylates) and/oi adjuvants.
• emulsifiers e.g carbomei, hydroxypropyl cellulose, sodium lauryl sulfate
• poiymei coatings e g , poloxamers or poloxamines
• coating and film forming agents e.g. ethyl cellulose, acrylates, polymethaciylates
• hie phaimaceutical compositions provided herein are controlled release compositions, i.e. compositions in which the SARM compound is released over a period of time after administration.
• Controlled or sustained release compositions include fo ⁇ nulation in lipophilic depots (e.g. fatty acids, waxes, oils)
• the composition is an immediate release composition, i,e a composition in which all of the SARM compound is released immediately after administration
• the phaimaceutical composition can be delivered in a controlled release system.
• the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, oi othei modes of administration.
• a pump may be used (see Langer, supra; Sefton, CRC Crit. Ref Biomed. Eng. 14:201 (1987); Buchwald et al , Surgery 88:507 (1980); Saudek et al., N. Engl. J, Med. 321:574 (1989)
• polymeric materials can be used.
• a controlled release system can be placed in proximity to hie therapeutic target, i.e., hie brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in hie review by Langer (Science 249:1527-1533 (1990).
• compositions may also include incorporation of the active material into or onto particulate preparations of polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc, or onto liposomes, micro-emulsions, micelles, unilamellar or mulhlamellai vesicles, eiytliiocyte ghosts, or spheroplasts.)
• polymeric compounds such as polylactic acid, polglycolic acid, hydrogels, etc.
• liposomes such as polylactic acid, polglycolic acid, hydrogels, etc.
• Such compositions will influence the physical state, solubility, stability, rate of in vivo release, and rate of in vivo clearance.
• Also comprehended by the invention are particulate compositions coated with polymers (e g poloxameis oi poloxamines) and the compound coupled to antibodies directed against tissue-specific receptois, ligands or antigens oi coupled to ligands of tissue-specific receptois.
• polymers e g poloxameis oi poloxamines
• Also comprehended by hie invention are compounds modified by the covalent attachment of water-soluble polymers such as polyethylene glycol, copolymers of polyethylene glycol and polypropylene glycol, carboxymethyl cellulose, dextian, polyvinyl alcohol, polyvinylpyrrolidone or polyproline.
• the modified compounds are known to exhibit substantially longer half-lives in blood following intravenous injection than do the corresponding unmodified compounds (Abuchowski et al, 1981; Newmaik et al., 1982; and Katie et al., 1987).
• Such modifications may also inciease the compomid's solubility in aqueous solution, eliminate aggregation, enhance the physical and chemical stability of the compound, and greatly reduce the immunogenicity and reactivity of the compound.
• the desired in vivo biological activity may be achieved by the administration of such polymer-compound abducts less frequently or in lower doses than with the unmodified compound,
• compositions that contain an active component are well undeistood in the art, for example by mixing, granulating, oi tablet-forming processes
• the active therapeutic ingredient is often mixed with excipients that aie pharmaceutically acceptable and compatible with the active ingredient.
• the SARM agents oi their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are mixed with additives customary foi this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, haid or soft gelatin capsules, aqueous, alcoholic or oily solutions.
• the SARM agents or their physiologically tolerated derivatives such as salts, esters, N-oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable foi this purpose, foi example, solubilizers or other,
• An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms.
• Pharmaceutically acceptable salts include the acid addition salts (fonned with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, oi such organic acids as acetic, oxalic, tartaric, mandelic, and the like Salts formed from hie free caiboxyl groups can also be derived from inoiganic bases such as, for example, sodium, potassium, ammonium, calcium, oi feiiic hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, piocaine, and the like.
• hie salts of the SARM will be pharmaceutically acceptable salts
• Other salts may, however, be useful in the preparation of the compounds accoiding to the invention oi of their pharmaceutically acceptable salts.
• Suitable phaimaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be foimed by mixing a solution of the compound according to the invenhon with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid,
• a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbon
• administering refers to bringing a subject in contact with a SARM compound of the piesent invention
• administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i e in cells or tissues of living organisms, for example humans.
• the present invention encompasses administering the compounds of the piesent invention to a subject.
• the temi "contacting" means that the SARM compound of the present invention is in oduced into a subject receiving treatment, and the SARM compound is allowed to come in contact with the AR in vivo.
• the methods of the present invention comprise administering a SARM compound as the sole active ingredient.
• methods for treating and/oi preventing bone-related disorders which comprise administering the SARM compounds in combination with one or more therapeutic agents.
• agents include, but aie not limited to: LHRH analogs, reversible anti-androgens, O 2005/060647
• anti-estiogens anticancer drugs, 5-alpha reductase inhibitors, aromatase inhibitors, progestins, agents acting through other nuclear hormone receptois, selective estrogen receptoi modulators (SERM), progesterone, estrogen, PDE5 inhibitors, apomorphine, bisphosphonate, and one or more additional SARMS,
• SERM selective estrogen receptoi modulators
• the methods of the piesent invention comprise administering the SARM compound in combination with an LHRH analog.
• the methods of the present invention comprise administering a SARM compound in combination with a reversible anti-androgen.
• the methods of the present invention comprise administering a SARM compound in combination with an aiiti-estiogen.
• the methods of the piesent invention comprise administering a SARM compound in combination with an anticancer drag.
• the methods of the present invention comprise administering a SARM compound in combination with a 5-alpha reductase inhibitor.
• the methods of the present invention comprise administering a SARM compound in combination with an aromatase ir ⁇ ibitoi. In another embodiment, the methods of the present invention comprise administering a SARM compound in combination with a progestin. In another embodiment, the methods of the piesent invention comprise administering a SARM compound in combination with an agent acting tlirough other nuclear hoimone receptois.
• hie methods of the present invention comprise administering a SARM compound in combination with a selective estrogen receptor modulator (SERM), In another embodiment, the methods of the present invention comprise administering a SARM compound in combination with a progesterone In another embodiment, the methods of hie present invention comprise administering a SARM compound in combination with an estrogen, In another embodiment, the methods of the present invention comprise administering a SARM compound in combination with a PDE5 inhibitor In another embodiment, the methods of the present invention comprise administering a SARM compound in combination with apomorphine, In another embodiment, the methods of the piesent invention comprise administering a SARM compoimd in combination with a bisphosphonate. In another embodiment, the methods of the present invention comprise administering a SARM compound, in combination with one or more additional SARMS. [000299]
• Step 1 Synthesis of (2R)-l-Methacryloylpyrrolidin-2-carboxylic Acid (Precursor compound A)
• Step 2 Synthesis of (3R,8aR)-3-BromomethyI-3-methyl-tetrahvdro-pyrroIof2,lcI [1,4] oxazine- 4-dione (Precursor compound B)
• Step 4 Synthesis of N-[4-Nitro-3-(trifluoromethyl)phenvn-(2R)-3-bromo-2-hvdroxy-2-methvIpropanam ide (compound #4 in Figure 1).
• Step 5 N-[4-nitro-3-trifluoromethyl)phenylI-(2S)-3-f4-(acetylamino) phenoxyl-2-hydroxy-2-methylpropanamide (Compound VIII; compound #6 in Figure 1).
• SARM compounds were used as starting point to synthesize phosphoric acid estei- modified and phosphoric acid-diethyl ester- modified prodrugs.
• the following protocol describes the preparation of SARM prodrugs from Compound XI.
• the protocol is generalizable, however, to all SARM compounds of the present invention.
• Phosphoric acid 1 -(4-cyano-3-trifluoiOmethyl-phenylcarbamoyl)-2-(4-fluoro-phenoxy)-l -methyl-ethyl ester diethyl ester (shuclure 7 in Figure 2) was synthesized as follows: To a stirred mixture of
• the obtained cleai solution was stirred at room temperature for 30 min Ethyl acetate was added to the reaction mixture, and the phases were separated.
• the oiganic phase was washed with 0.1N NaOH, and the combined aqueous phases were brought to pH 5 and extracted with ethyl acetate.
• Phosphoric acid mono-[ 1 -(4-cyano-3-trifluoromethyl-phenylcarbamoyl)-2-(4-fluoro-phenoxy)- 1 -methyl- ethyl] ester (structure 8 in Figure 2) was synthesized from stmcture 7 as follows: To a stined cold solution of structuie 7 (0.353 g, 0.6809 mmol) in anhydrous methylene chloride (10 mL), was added dropwise iodotrimehiylsilane (0,817 g, 4,0854 mmol) under a argon atmosphere and at 0 C The mixture was stirred for 1 h at 0 C and for 1 h O 2005/060647 at room temperature.
• SARM compounds exhibit a higher ratio of anabolic to androgenic activity than testosterone
• the SARM compounds described herein and their pro-drugs were designed, synthesized and evaluated for in-vitro and in-vivo pharmacologic activity.
• the in-viiro androgen receptor binding affinity and ability to maintain androgen dependent tissue growth in castrated animals was studied. Androgenic activity was monitored as the ability of the SARM compounds to maintain and/or stimulate the growth of the prostate and seminal vesicles, as measured by weight.
• Anabolic activity was monitored as the ability of the SARM compounds to maintain and/or stimulate the growth of the levator ani muscle, as measured by weight.
• tissue-selective androgenic and anabolic activity i.e., differing androgenic and anabolic potency
• testes were removed via a midline sciotal incision, with steator suture being used to ligate supia-testiculai tissue prioi to smgical removal of each testis.
• the surgical wound site was closed with steumble stainless steel wound clips, and the site cleaned with betadine, The animals were allowed to recover on a sterile pad (until able to stand) and then returned to their cage.
• weights of all organs were normalized to body weight, and analyzed for any statistical significant difference by single-factor ANOVA.
• the weights of prostate and seminal vesicle were used as indexes foi evaluation of androgenic activity, and the levatoi ani muscle weight was used to evaluate the anabolic activity
• Compound VIII Compared with testosterone propionate, Compound VIII exhibited a greatei potency and intrinsic activity in increasing the weight of levator ani muscle, while having a lowei potency and inhinsic activity in increasing the weights of prostate and seminal vesicle. At a dose as low as 0.3 mg/day, Compound VIII was able to maintain the levator ani muscle weight of castrated animals at the level of intact animals
• Compound IX significantly increased levatoi ani muscle weights without stimulate prostate and seminal vesicle growth (i e , the prostate and seminal vesicle weights were less than 20% of that observed in intact animals oi in animals treated with testosterone propionate).
• AR stimulation in androgenic tissues is a general property of SARMS, and is not particular to Compound VIII.
• Table 2 Effect of Compound VIII and TP on Plasma FSFI levels.
• Control Compound VIII TP (0.5 mg/day) (0.5 mg/day) 68.6 ⁇ 6.3 1 J 69.6 ⁇ 11.7 u 58.0 ⁇ 6.9 * ⁇ l
• Control Compound XXI TP (0.5 mg/day) (0.5 mg/day) __ ⁇ 8.704 ⁇ 1.709 u 8.644 ⁇ 2.799 T ⁇ 6.702 ⁇ 1.513 ⁇ *
• Compounds VIII and IX exhibited anabolic activity, maintaining the weight of levator ani muscle after removal of endogenous androgen. Selectivity of the anabolic activity was greater than testosterone propionate.
• Compound IV does not suppress FSH levels at doses that are capable of eliciting maximal stimulation of levatoi ani muscle growth.
• SARMS have therapeutic applications in males and females for modulation of fertility, erythropoiesis, osteoporosis, sexual libido and in men with or at high risk for prostate cancer.
• EXAMPLE 5 Pharmacokinetics of Compound VIII in Dogs
• the pharmacokinetics of S-Compound VIII were characterized in beagle dogs
• a four-treatment, four-period crossover design was utilized in hie study, which involved a total of six beagle dogs, three of each gender.
• Each animal received a 3 mg/kg IV dose, a 10 mg/kg IV dose, a 10 mg/kg PO dose in solution, and a 10 mg/kg PO dose in capsule, in a randomly assigned order. There was a one-week washout period between treatments.
• Plasma samples were collected for up to 72 hr after drug administration Plasma Compound VIII concentrations were analyzed by a validated HPLC method.
• a reversed phase high pressure liquid chiomatograph (PIPLC) assay was developed to quantitate Compound VIII concentrations in dog plasma.
• Dog blood samples were obtained by venipuncture and centrifuged at lOOOg for 15 minutes. Samples weie stored frozen at -20°C until analysis. Individual samples were rapidly thawed and an aliquot (0.5 ml) was spiked with internal standard (20 ⁇ l of a 200 ⁇ g/ml aqueous solution of CM-II-87). An aliquot of 1 ml of acetonitrile was added to the samples to precipitate plasma proteins. The samples were vortexed and then centrifuged at lOOOg for 15 minutes.
• the supernatant was decanted into glass extraction tubes and 7.5 ml of ethyl acetate was added.
• the extraction mixture was left at room temperature foi 20 minutes, and vortexed several times during this interval.
• the samples were then centrifuged at lOOOg foi 10 minutes, and the organic phase was removed and placed in conical-bottomed glass tubes. The organic phase was evapoiated under nitrogen.
• the samples were reconstituted in 200 ⁇ l of mobile phase (35:65 acetonitrile:water) and transferred to an autosampler vial for HPLC injection (Waters 717 plus autosamplei, Watei s Corp., Milford, MA).
• the isocratic mobile phase of 35% (v/v) acetonitrile in watei was pumped at a flow rate of 1 ml/min (Model 510, Waters Corp.), The stationary phase was a C18 reversed phase column (Novapak C18, 3.9 x 150 mm). Analytes were monitored with UV detection at 270 nm (Model 486 absorbance detector, Waters Corp.). Retention times for Compound VIII and CM-II-87 were 11.1 and 16.9 minutes, respectively. Chromatography data was collected and analyzed using Millennium software Plasma concentrations of Compound VIII in each sample weie determined by comparison to calibration curves. Calibration curves were conshucted by adding known amounts of Compound VIII to dog plasma.
• Mass spectra were determined on a Bruker-HP Esquire LC System. Elemental analyses were performed by Atlantic Microlab Inc. (Norcross, GA), and found values were within 0,4 % of hie theoretical values. Routine thin-layer chromatography (TLC) was perfoimed on silica gel on aluminum plates (silica gel 60 F 254, 20 x 20 cm, Aldrich Chemical Company Inc., Milwaukee, WI), Flash chromatography was performed on silica gel (Merck, grade 60, 230-400 mesh, 60) Tetrahydrofuran (THF) was dried by distillation over sodium metal. Acetonitrile (MeCN) and methylene chloride (CH 2 C1 2 ) were dried by distillation from P 2 Os
• mice are weighed and randomly distributed into twelve (12) groups, with 7 animals per group. Treatment groups are depicted in Table 4 On day one of the drug treatment, animals in all groups are individually removed from the cage and anesthetized with an intraperitoneal dose of ketamine/xylazine (87/13 mg/kg). When appropriately anesthetized (i.e. no response to toe pinch), the animals' ears are marked for identification purposes. Animals are then placed on a sterile pad and theii abdomen and scrotum washed with betadine and 70% alcohol.
• testes are removed via a midline scrotal incision, with steator clips used to ligate supra-testicular tissue prior to suigical removal of each testis.
• the surgical wound site is closed with stevette stainless steel wound clips, and antibiotic ointment is applied to the incision site.
• mice in group 1 received sham surgery (midline incision with subsequent closure of the skin).
• the appropriate dose is administeied by oral gavage or subcutaneous injection. Dosing continues once daily for ten days, after which the mice are anesthetized with ketamine/xylazine and then euthanized by exsangui ⁇ ation. A portion of the blood is centrifuged at 3,000 x g for I minute, and the plasma layer is removed and frozen at -20°C The ventral prostates, seminal vesicles, and levator ani muscles are removed, cleared of extraneous tissue, and weighed.
• the oigan weights are normalized to body weight, and analyzed for any statistical significant difference by single-factor ANOVA.
• the weights of prostate and seminal vesicle are used as indexes to evaluate androgenic activity, and the levator ani muscle weight was used to evaluate anabolic activity.
• SARM prodmgs aie found to have anabolic and androgenic activity in a similar ratio to the parent SARM compounds This initial experiment is not designed to measure the exact potency of the SARM prodmgs, but rather to establish that they exhibit biological activity similar to the parent compounds.
• SARM prodrugs are metabolized into the parent SARM compound
• SARM prodrugs exhibit a lower affinity of the AR than the respective parent compounds
• SARM prodrugs exhibit different aqueous solubility from the parent SARM compound
• Aqueous solubility of SARM prodrugs shown to have biological activity are ascertained and compared to the parent SARM compounds.
• the prodrug modifications are found to alter solubility.
• increased aqueous solubility is advantageous foi bioavailability because in increases dissoluhon of the drug in the gastrointestinal tract.
• decreased aqueous solubility increases bioavailability by increasing penetiation of the drag tlnough mucous membranes such as the gastrointestinal epithelium.
• Example 7 The experiment described in Example 7 is repeated, this time using 6 different concentrations of each compound.
• the results show that the prodmg modifications confer increased potency to the drags.
• the modifications improve potency by improving hie bioavailabililty of the di ⁇ gs.
• the modifications inciease the half-life of the compounds.
• the modifications fostei concentration of the compound in tissues where its biological activity is needed; i e bone tissue, muscle tissue, accessory sexual organs, etc.

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